Substituted bridged diazepane derivatives and use thereof as TASK-1 and TASK-3 inhibitors

ABSTRACT

The present application relates to novel imidazopyridinyl- or imidazopyrimidinyl-substituted, bridged 1,4-diazepane derivatives of formula (I), to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of respiratory disorders including, sleep-related respiratory disorders such as obstructive sleep apnoeas and central sleep apnoeas and snoring. Formula (I) in which the ring Q represents a bridged 1,4-diazepane cycle.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage application under 35 U.S.C. § 371of International Application No. PCT/EP2018/064980, filedinternationally on Jun. 7, 2018, which claims the benefit ofInternational Application No. PCT/CN2017/088237, filed Jun. 14, 2017.

The present application relates to novel imidazopyridinyl- orimidazopyrimidinyl-substituted, bridged 1,4-diazepane derivatives, toprocesses for their preparation, to their use alone or in combinationsfor the treatment and/or prevention of diseases, and to their use forpreparing medicaments for the treatment and/or prevention of diseases,in particular for treatment and/or prevention of respiratory disordersincluding, sleep-related respiratory disorders such as obstructive sleepapnoeas and central sleep apnoeas and snoring.

Potassium channels are virtually ubiquitous membrane proteins which areinvolved in a large number of different physiological processes. Thisalso includes the regulation of the membrane potential and the electricexcitability of neurons and muscle cells. Potassium channels are dividedinto three major groups which differ in the number of transmembranedomains (2, 4 or 6). The group of potassium channels where twopore-forming domains are flanked by four transmembrane domains isreferred to as K2P channels. Functionally, the K2P channels mediate,substantially time- and voltage-independently, K⁺ background currents,and their contribution to the maintenance of the resting membranepotential is crucial. The family of the K2P channels includes 15 memberswhich are divided into six subfamilies, based on similarities insequence, structure and function: TWIK, TREK, TASK, TALK, THIK andTRESK.

Of particular interest are TASK-1 (KCNK3 or K2P3.1) and TASK-3 (KCNK9 orK2P9.1) of the TASK (TWIK-related acid-sensitive K⁺ channel) subfamily.Functionally, these channels are characterized in that, duringmaintenance of voltage-independent kinetics, they have “leak” or“background” streams flowing through them, and they respond to numerousphysiological and pathological influences by increasing or decreasingtheir activity. A characteristic feature of TASK channels is thesensitive reaction to a change of the extracellular pH: at acidic pH thechannels are inhibited, and at alkaline pH they are activated.

TASK-1 is expressed mainly in the central nervous system and in thecardiovascular system. Relevant expression of TASK-1 was demonstrated inthe brain, in spinal ganglia, in motoneurons of the Nervus hypoglossusand Nervus trigeminus, in the heart, Glomus caroticum, the pulmonaryartery, aorta, lung, pancreas, placenta, uterus, kidney, adrenal gland,small intestine and stomach, and also on T lymphocytes. TASK-3 isexpressed mainly in the central nervous system. Relevant expression ofTASK-3 was demonstrated in the brain, in motoneurons of the Nervushypoglossus and Nervus trigeminus and in neuroepithelial cells of theGlomus caroticum and the lung, and also on T lymphocytes. A lowerexpression is found in the heart, stomach, testicular tissue and adrenalgland.

TASK-1 and TASK-3 channels play a role in respiratory regulation. Bothchannels are expressed in the respiratory neurons of the respiratorycentre in the brain stem, inter alia in neurons which generate therespiratory rhythm (ventral respiratory group with pre-Botzingercomplex), and in the noradrenergic Locus caeruleus, and also inserotonergic neurons of the raphe nuclei. Owing to the pH dependency,here the TASK channels have the function of a sensor which translateschanges in extracellular pH into corresponding cellular signals [Baylisset al., Pflugers Arch. 467, 917-929 (2015)]. TASK-1 and TASK-3 are alsoexpressed in the Glomus caroticum, a peripheral chemoreceptor whichmeasures pH, O₂ and CO₂ content of the blood and transmits signals tothe respiratory centre in the brain stem to regulate respiration. It wasshown that TASK-1 knock-out mice have a reduced ventilatory response(increase of respiratory rate and tidal volume) to hypoxia and normoxichypercapnia [Trapp et al., J. Neurosci. 28, 8844-8850 (2008)].Furthermore, TASK-1 and TASK-3 channels were demonstrated in motoneuronsof the Nervus hypoglossus, the XIIth cranial nerve, which has animportant role in keeping the upper airways open [Berg et al., J.Neurosci. 24, 6693-6702 (2004)].

In a sleep apnoea model in the anaesthetized pig, intranasaladministration of a potassium channel blocker which blocks the TASK-1channel in the nanomolar range led to inhibition of collapsibility ofthe pharyngeal respiratory musculature and sensitization of the negativepressure reflex of the upper airways. It is assumed that intranasaladministration of the potassium channel blocker depolarizesmechanoreceptors in the upper airways and, via activation of thenegative pressure reflex, leads to increased activity of the musculatureof the upper airways, thus stabilizing the upper airways and preventingcollapse. By virtue of this stabilization of the upper airways, the TASKchannel blockade may be of great importance for obstructive sleep apnoeaand also for snoring [Wirth et al., Sleep 36, 699-708 (2013); Kiper etal., Pflugers Arch. 467, 1081-1090 (2015)].

Obstructive sleep apnoea (OSA) is a sleep-related respiratory disorderwhich is characterized by repeat episodes of obstruction of the upperairways. When breathing in, the patency of the upper airways is ensuredby the interaction of two opposite forces. The dilative effects of themusculature of the upper airways counteract the negative intraluminalpressure, which constricts the lumen. The active contraction of thediaphragm and the other auxiliary respiratory muscles generates anegative pressure in the airways, thus constituting the driving forcefor breathing. The stability of the upper respiratory tract issubstantially determined by the coordination and contraction property ofthe dilating muscles of the upper airways.

The Musculus genioglossus plays a decisive role in the pathogenesis ofobstructive sleep apnoea. The activity of the Musculus genioglossusincreases with decreasing pressure in the pharynx in the sense of adilative compensation mechanism. Innervated by the Nervus hypoglossus,it drives the tongue forward and downward, thus widening the pharyngealairway [Verse et al., Somnologie 3, 14-20 (1999)]. Tensioning of thedilating muscles of the upper airways is modulated inter alia viamechanoreceptors/stretch receptors in the nasal cavity/pharynx[Bouillette et al., J. Appl. Physiol. Respir. Environ. Exerc. Physiol.46, 772-779 (1979)]. In sleeping patients suffering from serious sleepapnoea, under local anaesthesia an additional reduction of the activityof the Musculus genioglossus can be observed [Berry et al., Am. J.Respir. Crit. Care Med. 156, 127-132 (1997)]. Patients suffering fromobstructive sleep apnoea have high mortality and morbidity as a resultof cardiovascular disorders such as hypertension, myocardial infarctionand stroke [Vrints et al., Acta Clin. Belg. 68, 169-178 (2013)].

In the case of central sleep apnoea, owing to impaired brain functionand impaired respiratory regulation there are episodic inhibitions ofthe respiratory drive. Central respiratory disorders result inmechanical respiratory arrests, i.e. during these episodes there is nobreathing activity; temporarily, all respiratory muscles including thediaphragm are at rest. In the case of central sleep apnoea, there is noobstruction of the upper airways.

In the case of primary snoring, there is likewise no obstruction of theupper airways. However, owing to the constriction of the upper airways,the flow rate of the air that is inhaled and exhaled increases. This,combined with the relaxed musculature, causes the soft tissues of theoral cavity and the pharynx to flutter in the stream of air. This gentlevibration then generates the typical snoring noises.

Obstructive snoring (upper airway resistance syndrome, heavy snoring,hypopnoea syndrome) is caused by repeat partial obstruction of the upperairways during sleep. This results in an increased respiratoryresistance and thus in an increase in work of breathing withconsiderable fluctuations in intrathoracic pressure. During inspiration,the negative intrathoracic pressure may reach values similar to thosethat are encountered as a result of complete airway obstruction duringobstructive sleep apnoea. The pathophysiological consequences for heart,circulation and sleep quality correspond to those of obstructive sleepapnoea. As in obstructive sleep apnoea, the pathogenesis is assumed tobe an impaired reflex mechanism of the pharynx-dilating muscles duringinspiration when sleeping. Frequently, obstructive snoring is thepreliminary stage of obstructive sleep apnoea [Hollandt et al., HNO 48,628-634 (2000)].

In addition, TASK channels also appear to play a role in the apoptosisof neurons. In the animal model of myelin oligodendrocyte glycoprotein(MOG)-induced autoimmune encephalomyelitis, an animal model of multiplesclerosis, TASK-1 knock-out mice showed reduced neuronal degeneration.By preventing neuronal apoptosis, inhibition of TASK channels appears toact neuroprotectively, and may thus be of interest for the treatment ofneurodegenerative disorders [Bittner et al., Brain 132, 2501-2516(2009)].

Furthermore, it has been described that T lymphocytes express TASK-1 andTASK-3 channels and that inhibition of these channels leads to reducedcytokine production and proliferation after stimulation of Tlymphocytes. The selective inhibition of TASK channels on T lymphocytesimproved the course of the disease in an animal model of multiplesclerosis. The blockade of TASK channels may therefore also be ofimportance for treatment of autoimmune disorders [Meuth et al., J. Biol.Chem. 283, 14559-14579 (2008)].

TASK-1 and TASK-3 are also expressed in the heart [Rinné et al., J. Mol.Cell. Cardiol. 81, 71-80 (2015)]. Since TASK-1 is expressed particularlystrongly in the nervous stimuli conduction system and in the atrium,this channel may have a role in disrupting stimuli conduction ortriggering supraventricular arrhythmias. In the heart, TASK-1 appears tocontribute to a background current which for its part contributes tomaintenance of the resting potential, to action potential duration andto repolarization [Kim et al., Am. J. Physiol. 277, H1669-1678 (1999)].Using human heart muscle cells, it was shown that blockade of the TASK-1ion current results in a longer action potential [Limberg et al., Cell.Physiol. Biochem. 28, 613-624 (2011)]. Furthermore, for TASK-1 knock-outmice a prolonged QT time was demonstrated [Decher et al., Cell. Physiol.Biochem. 28, 77-86 (2011)]. Inhibition of TASK channels may therefore beof importance for the treatment of cardiac arrythmias, in particularatrial fibrillation.

In certain vessels, TASK channels also appear to play a role in theregulation of the vascular tone. A relevant expression of TASK-1 wasnoticed in smooth muscles of pulmonary and mesenteric arteries. Instudies on smooth muscle cells of human pulmonary arteries, it was shownthat TASK-1 plays a role in the regulation of the pulmonary vasculartone. TASK-1 may be involved in hypoxic and acidosis-induced pulmonaryvasoconstriction [Tang et al., Am. J. Respir. Cell. Mol. Biol. 41,476-483 (2009)].

In glomerulosa cells of the adrenal cortex, TASK-1 plays a role inpotassium conductivity [Czirjak et al., Mol. Endocrinol. 14, 863-874(2000)].

Possibly, TASK channels also play an important role in apoptosis andtumorigenesis. In breast cancer, colon cancer and lung cancer biopsiesand also in metastasizing prostate cancer and in melanoma cells, TASK-3has been found to be strongly overexpressed [Mu et al., Cancer Cell 3,297-302 (2003); Kim et al., APMIS 112, 588-594 (2004); Pocsai et al.,Cell. Mol. Life Sci. 63, 2364-2376 (2006)]. A point mutation at theTASK-3 channel, which switches off the channel function, simultaneouslycancels the tumour-forming action (proliferation, tumour growth,apoptosis resistance) [Mu et al., Cancer Cell 3, 297-302 (2003)].Overexpression of TASK-3 and TASK-1 in a murine fibroblast cell line (C8cells) inhibits intracellular apoptosis routes [Liu et al., Brain Res.1031, 164-173 (2005)]. Accordingly, the blockade of TASK channels mayalso be relevant for the treatment of various neoplastic disorders.

Therefore, it is an object of the present invention to provide novelsubstances which act as potent and selective blockers of TASK-1 andTASK-3 channels and, as such, are suitable in particular for thetreatment and/or prevention of respiratory disorders includingsleep-related respiratory disorders such as obstructive and centralsleep apnoea and snoring, and also other disorders.

US 2002/0022624-A1 describes various azaindole derivatives includingimidazo[1,2-a]pyridines as substance P antagonists for the treatment ofCNS disorders. WO 2009/143156-A2 discloses2-phenylimidazo[1,2-a]pyridine derivatives which, as modulators ofGABA_(A) receptors, are likewise suitable for treating CNS disorders. WO2011/113606-A1 and WO 2012/143796-A2 disclose bicyclic imidazolederivatives suitable for the treatment of bacterial infections andinflammatory disorders. EP 2 671 582-A1 discloses further bicyclicimidazole derivatives and options for their therapeutic use asinhibitors of T type calcium channels. WO 2012/130322-A1 claims2,6-diaryl-3-(1,4-diazepanylmethyl)imidazo[1,2-a]pyridines which, byvirtue of their HIF-1 inhibiting activity, are suitable in particularfor the treatment of inflammatory and hyperproliferative disorders. WO2014/187922-A1 discloses various2-phenyl-3-(heterocyclomethyl)imidazo[1,2-a]pyridine and-imidazo[1,2-a]pyrazine derivatives as inhibitors of glucosetransporters (GLUT) which can be employed for treating inflammatory,proliferative, metabolic, neurological and/or autoimmune disorders. WO2015/144605-A1 and WO 2017/050732-A1, inter alia, describe acylatedbicyclic amine compounds suitable as inhibitors of autotaxin and oflysophosphatidic acid production for the treatment of various disorders.WO 2016/084866-A1 and WO 2016/088813-A1 disclose acylated bridgedpiperazine derivatives and WO 2016/085783-A1 and WO 2016/085784-A1acylated 1,4-diazepane derivatives as orexin receptor antagonists whichcan be used for treating neurodegenerative, neurological and psychiatricdisorders, mental disorders and eating and sleep disorders, inparticular insomnia.

Furthermore, the compounds

-   (2-chlorophenyl)    {4-[(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl]-1,4-diazepan-1-yl}methanone    [CAS Registry No. 1299434-44-8]-   and-   {4-[(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl]-1,4-diazepan-1-yl}(pyridin-2-yl)methanone    [CAS Registry No. 12888 72-88-7]    are indexed by Chemical Abstracts as “Chemical Library” substances    without literature reference; a medicinal-therapeutic application of    these compounds has hitherto not been described.

The present invention provides compounds of the general formula (I)

in whichthe ring Q represents a bridged 1,4-diazepane cycle of the formula

-   -   in which * denotes the bond to the adjacent methylene group and        ** the bond to the carbonyl group,

-   A represents CH or N,

-   D represents CH or N,

-   R¹ represents halogen, cyano, (C₁-C₄)-alkyl, cyclopropyl or    cyclobutyl    -   where (C₁-C₄)-alkyl may be up to trisubstituted by fluorine and        cyclopropyl and cyclobutyl may be up to disubstituted by        fluorine,

-   and

-   R² represents (C₄-C₆)-cycloalkyl in which a ring CH₂ group may be    replaced by —O—,

-   or

-   R² represents a phenyl group of the formula (a), a pyridyl group of    the formula (b) or (c) or an azole group of the formula (d),    (e), (f) or (g),

-   -   in which *** marks the bond to the adjacent carbonyl group and    -   R³ represents hydrogen, fluorine, chlorine, bromine or methyl,    -   R⁴ represents hydrogen, fluorine, chlorine, bromine, cyano,        (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,        -   where (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy may each be up to            trisubstituted by fluorine,    -   R⁵ represents hydrogen, fluorine, chlorine, bromine or methyl,    -   R⁶ represents hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy,        oxetan-3-yloxy, tetrahydrofuran-3-yloxy,        tetrahydro-2H-pyran-4-yloxy, mono-(C₁-C₃)-alkylamino,        di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl,        -   where (C₁-C₃)-alkoxy may be up to trisubstituted by            fluorine,    -   R⁷ represents hydrogen, fluorine, chlorine, bromine,        (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,    -   R^(8A) and R^(8B) are identical or different and independently        of one another represent hydrogen, fluorine, chlorine, bromine,        (C₁-C₃)-alkyl, cyclopropyl or (C₁-C₃)-alkoxy,        -   where (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy may each be up to            trisubstituted by fluorine,    -   R⁹ represents hydrogen, (C₁-C₃)-alkyl or amino    -   and    -   Y represents O or S, or

-   R² represents an —OR¹⁰ or —NR¹¹R¹² group in which    -   R¹⁰ represents (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or        [(C₃-C₆)-cycloalkyl]methyl,    -   R¹¹ represents hydrogen or (C₁-C₃)-alkyl    -   and    -   R¹² represents (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or        benzyl,        -   where (C₁-C₆)-alkyl may be up to trisubstituted by fluorine,        -   and        -   where phenyl and the phenyl group in benzyl may be up to            trisubstituted by identical or different radicals selected            from the group consisting of fluorine, chlorine, methyl,            ethyl, trifluoromethyl, methoxy, ethoxy and            trifluoromethoxy,    -   or    -   R¹¹ and R¹² are attached to one another and, together with the        nitrogen atom to which they are bonded, form a pyrrolidine,        piperidine, morpholine or thiomorpholine ring,

-   and the salts, solvates and solvates of the salts thereof.

Inventive compounds are the compounds of the formula (I) and the salts,solvates and solvates of the salts thereof, the compounds of theformulae (I-A), (I-B), (I-C) and (I-D) below that are encompassed byformula (I) and the salts, solvates and solvates of the salts thereof,and the compounds cited hereinafter as working examples that areencompassed by formula (I) and the salts, solvates and solvates of thesalts thereof, if the compounds cited hereinafter that are encompassedby formula (I) are not already salts, solvates and solvates of thesalts.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the compounds of the invention. Alsoencompassed are salts which are not themselves suitable forpharmaceutical applications but can be used, for example, for theisolation, purification or storage of the compounds of the invention.

Physiologically acceptable salts of the compounds of the inventioninclude acid addition salts of mineral acids, carboxylic acids andsulfonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroaceticacid, propionic acid, succinic acid, fumaric acid, maleic acid, lacticacid, tartaric acid, malic acid, citric acid, gluconic acid, benzoicacid and embonic acid.

Solvates in the context of the invention are described as those forms ofthe compounds of the invention which form a complex in the solid orliquid state by coordination with solvent molecules. Hydrates are aspecific form of the solvates in which the coordination is with water.Solvates preferred in the context of the present invention are hydrates.

The compounds of the invention may, depending on their structure, existin different stereoisomeric forms, i.e. in the form of configurationalisomers or else, if appropriate, as conformational isomers (enantiomersand/or diastereomers, including those in the case of atropisomers). Thepresent invention therefore encompasses the enantiomers anddiastereomers, and the respective mixtures thereof. Thestereoisomerically homogeneous constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably employed for the purpose,especially HPLC chromatography on chiral or achiral separation phases.In the case of chiral amines as intermediates or end products,separation is alternatively also possible via diastereomeric salts usingenantiomerically pure carboxylic acids.

If the compounds of the invention can occur in tautomeric forms, thepresent invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds of the invention. An isotopic variant of a compound of theinvention is understood here to mean a compound in which at least oneatom within the compound of the invention has been exchanged for anotheratom of the same atomic number, but with a different atomic mass fromthe atomic mass which usually or predominantly occurs in nature.Examples of isotopes which can be incorporated into a compound of theinvention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variantsof a compound according to the invention, especially those in which oneor more radioactive isotopes have been incorporated, may be beneficial,for example, for the examination of the mechanism of action or of theactive ingredient distribution in the body; due to the comparativelyeasy preparability and detectability, especially compounds labeled with³H or ¹⁴C isotopes are suitable for this purpose. In addition, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic benefits as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds of the invention may therefore possibly also constitutea preferred embodiment of the present invention. Isotopic variants ofthe compounds of the invention can be prepared by commonly usedprocesses known to those skilled in the art, for example by the methodsdescribed further down and the procedures described in the workingexamples, by using corresponding isotopic modifications of therespective reagents and/or starting compounds.

The present invention additionally also encompasses prodrugs of thecompounds of the invention. The term “prodrugs” refers here to compoundswhich may themselves be biologically active or inactive, but areconverted while present in the body, for example by a metabolic orhydrolytic route, to compounds of the invention.

In the context of the present invention, unless specified otherwise, thesubstituents and radicals are defined as follows:

In the context of the invention, (C₁-C₆-alkyl is a straight-chain orbranched alkyl radical having 1 to 6 carbon atoms. Examples include:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyland 3-hexyl.

In the context of the invention, (C₁-C₄)-alkyl is a straight-chain orbranched alkyl radical having 1 to 4 carbon atoms. Examples include:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl andtert-butyl.

In the context of the invention, (C₁-C₃)-alkyl is a straight-chain orbranched alkyl radical having 1 to 3 carbon atoms. Examples include:methyl, ethyl, n-propyl and isopropyl.

(C₁-C₃)-Alkoxy in the context of the invention is a straight-chain orbranched alkoxy radical having 1 to 3 carbon atoms. Examples include:methoxy, ethoxy, n-propoxy and isopropoxy.

Mono-(C₁-C₃)-alkylamino in the context of the invention is an aminogroup having a straight-chain or branched alkyl substituent having 1 to3 carbon atoms. Examples include: methylamino, ethylamino, n-propylaminoand isopropylamino.

Di-C₁-C₃)-alkylamino in the context of the invention is an amino grouphaving two identical or different straight-chain or branched alkylsubstituents each having 1 to 3 carbon atoms. Examples include:N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,N-methyl-N-n-propylamino, N-isopropyl-N-methylamino,N,N-di-n-propylamino, N-isopropyl-N-n-propylamino andN,N-diisopropylamino.

(C₁-C₃)-Alkylsulfanyl [also referred to as (C₁-C₃)-alkylthio] in thecontext of the invention is a straight-chain or branched alkyl radicalhaving 1 to 3 carbon atoms which is attached to the remainder of themolecule via a sulfur atom. Examples include: methylsulfanyl,ethylsulfanyl, n-propylsulfanyl and isopropylsulfanyl.

(C₃-C₆)-Cycloalkyl in the context of the invention is a monocyclicsaturated cycloalkyl group having 3 to 6 ring carbon atoms. Examplesinclude: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

(C₄-C₆)-Cycloalkyl in the context of the invention is a monocyclicsaturated cycloalkyl group having 4 to 6 carbon atoms. Examples include:cyclobutyl, cyclopentyl and cyclohexyl.

Halogen in the context of the invention includes fluorine, chlorine,bromine and iodine. Preference is given to fluorine, chlorine orbromine.

In the context of the present invention, all radicals which occur morethan once are defined independently of one another. When radicals in thecompounds of the invention are substituted, the radicals may be mono- orpolysubstituted, unless specified otherwise. Substitution by onesubstituent or by two identical or different substituents is preferred.Particular preference is given to substitution by one substituent.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   the ring Q represents a bridged 1,4-diazepane cycle of the formula

-   -   in which * denotes the bond to the adjacent methylene group and        ** the bond to the carbonyl group,

-   A represents CH or N,

-   D represents CH or N,

-   R¹ represents fluorine, chlorine, bromine, methyl, isopropyl,    tert-butyl, cyclopropyl or cyclobutyl

-   and

-   R² represents cyclobutyl, cyclopentyl or cyclohexyl

-   or

-   R² represents a phenyl group of the formula (a), a pyridyl group of    the formula (b) or an azole group of the formula (d), (e), (f) or    (g),

-   -   in which *** marks the bond to the adjacent carbonyl group and    -   R³ represents hydrogen, fluorine or chlorine,    -   R⁴ represents fluorine, chlorine, cyano, (C₁-C₃)-alkyl,        (C₁-C₃)-alkoxy or trifluoromethoxy,    -   R⁵ represents hydrogen, fluorine, chlorine, bromine or methyl,    -   R⁶ represents (C₁-C₃)-alkoxy, cyclobutyloxy or        (C₁-C₃)-alkylsulfanyl,        -   where (C₁-C₃)-alkoxy may be up to trisubstituted by            fluorine,    -   R^(8A) and R^(8B) are identical or different and independently        of one another represent hydrogen, chlorine, bromine,        (C₁-C₃)-alkyl or cyclopropyl,        -   where (C₁-C₃)-alkyl may be up to trisubstituted by fluorine,    -   R⁹ represents methyl or amino    -   and    -   Y represents O or S,

-   and the salts, solvates and solvates of the salts thereof.

A particular embodiment of the present invention relates to compounds ofthe formula (I) in which

-   the ring Q represents a bridged 1,4-diazepane cycle of the formula

-   -   in which * denotes the bond to the adjacent methylene group and        ** the bond to the carbonyl group,

-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   the ring Q represents a bridged 1,4-diazepane cycle of the formula

-   -   in which * denotes the bond to the adjacent methylene group and        ** the bond to the carbonyl group, and the salts, solvates and        solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   the ring Q represents a bridged 1,4-diazepane cycle of the formula

-   -   in which * denotes the bond to the adjacent methylene group and        ** the bond to the carbonyl group,

-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   A is CH and D is N,-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   A is N and D is CH,-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   R¹ is chlorine, bromine or isopropyl,-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   R² represents cyclopentyl or cyclohexyl,-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   R² is a phenyl group of the formula (a)

-   -   in which ** marks the bond to the adjacent carbonyl group,    -   R³ is hydrogen, fluorine or chlorine    -   and    -   R⁴ is fluorine, chlorine, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,

-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   R² is a pyridyl group of the formula (b)

-   -   in which ** marks the bond to the adjacent carbonyl group,    -   R⁵ is hydrogen, fluorine, chlorine, bromine or methyl    -   and    -   R⁶ represents (C₁-C₃)-alkoxy, cyclobutyloxy or        (C₁-C₃)-alkylsulfanyl,        -   where (C₁-C₃)-alkoxy may be up to trisubstituted by            fluorine,

-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   R² represents an azole group of the formula (d), (e) or (f)

-   -   in which ** marks the bond to the adjacent carbonyl group,    -   R^(8A) and R^(8B) are identical or different and independently        of one another represent hydrogen, chlorine, bromine,        (C₁-C₃)-alkyl or cyclopropyl,        -   where (C₁-C₃)-alkyl may be up to trisubstituted by fluorine,    -   and    -   Y represents O or S,

-   and the salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention relates tocompounds of the formula (I) in which

-   R² represents an azole group of the formula (g)

-   -   in which *** marks the bond to the adjacent carbonyl group    -   and    -   R⁹ represents (C₁-C₃)-alkyl or amino,

-   and the salts, solvates and solvates of the salts thereof.

In the context of the present invention, particular preference is givento compounds of the formula (I) in which

-   the ring Q represents a bridged 1,4-diazepane cycle of the formula

-   -   in which * denotes the bond to the adjacent methylene group and        ** the bond to the carbonyl group,

-   A represents CH or N,

-   D represents CH or N,

-   R¹ represents chlorine, bromine, isopropyl or cyclopropyl

-   and

-   R² represents cyclopentyl or cyclohexyl,

-   or

-   R² represents a phenyl group of the formula (a), a pyridyl group of    the formula (b) or an azole group of the formula (g),

-   -   in which *** marks the bond to the adjacent carbonyl group and    -   R³ represents hydrogen, fluorine or chlorine,    -   R⁴ represents fluorine, chlorine, methyl, isopropyl, methoxy or        ethoxy,    -   R⁵ represents hydrogen, fluorine, chlorine, bromine or methyl,    -   R⁶ represents methoxy, difluoromethoxy, trifluoromethoxy,        isopropoxy, cyclobutyloxy or methylsulfanyl    -   and    -   R⁹ represents methyl or amino,

-   and the salts, solvates and solvates of the salts thereof.

The individual radical definitions specified in the respectivecombinations or preferred combinations of radicals are, independently ofthe respective combinations of the radicals specified, also replaced asdesired by radical definitions of other combinations. Particularpreference is given to combinations of two or more of the abovementionedpreferred ranges.

The invention furthermore provides a process for preparing the compoundsof the formula (I) according to the invention, characterized in that acompound of the formula (II)

in which A, D and R¹ have the meanings given aboveis reacted in the presence of a suitable reducing agent either[A] with a compound of the formula (III)

-   -   in which R² and the ring Q have the meanings above    -   to give a compound of the formula (I)        or        [B] with a protected diazabicyclic system of the formula (IV)

-   -   in which the ring Q has the meaning given above    -   and    -   PG represents a suitable amino protecting group, for example        tert-butoxycarbonyl, benzyloxycarbonyl or        (9H-fluoren-9-ylmethoxy)carbonyl    -   at first to give a compound of the formula (V)

-   -   in which A, D, PG, R¹ and the ring Q have the meanings given        above,    -   then the protecting group PG is removed and the resulting        compound of the formula (VI)

-   -   in which A, D, R¹ and the ring Q have the meanings given above    -   is then reacted, depending on the specific meaning of the R²        radical,    -   [B-1] with a carboxylic acid of the formula (VII)

-   -   -   in which        -   R^(2A) represents (C₄-C₆)-cycloalkyl in which a ring CH₂            group may be replaced by —O—, or is a phenyl group of the            formula (a), a pyridyl group of the formula (b) or (c) or an            azole group of the formula (d), (e), (f) or (g), as            described above,

    -   with activation of the carboxylic acid function in (VII), or is        reacted with the corresponding acid chloride of the formula        (VIII)

-   -   in which R^(2A) has the meaning given above    -   to give a compound of the formula (I-A)

-   -   in which A, D, R¹, R^(2A) and the ring Q have the meanings given        above or    -   [B-2] with a chloroformate or carbamoyl chloride of the formula        (IX)

-   -   -   in which        -   R^(2B) is the —OR¹⁰ or —NR^(11A)R¹² group in which        -   R¹⁰ and R¹² have the meanings given above        -   and        -   R^(11A) has the definition of R¹¹ given above, but is not            hydrogen,

    -   to give a compound of the formula (I-B)

-   -   in which A, D, R¹, R^(2B) and the ring Q have the meanings given        above        or    -   [B-3] with an isocyanate of the formula (X)        R¹²—N═C═O  (X),        -   in which R¹² has the meaning given above,        -   to give a compound of the formula (I-C)

-   -   in which A, D, R¹, R¹² and the ring Q have the meanings given        above        and the compounds of the formulae (I), (I-A), (I-B) or (I-C)        thus obtained are optionally separated into their enantiomers        and/or diastereomers and/or optionally converted with the        appropriate (i) solvents and/or (ii) acids to the solvates,        salts and/or solvates of the salts thereof.

Suitable reducing agents for the process steps [A] (II)+(III)→(I) and[B] (II)+(IV)→(V) [reductive aminations] for such purposes are customaryalkali metal borohydrides such as sodium borohydride, sodiumcyanoborohydride or sodium triacetoxyborohydride; preference is given tousing sodium triacetoxyborohydride. The addition of an acid, such asacetic acid in particular, and/or of a dehydrating agent, for examplemolecular sieve or trimethyl orthoformate or triethyl orthoformate, maybe advantageous in these reactions.

Suitable solvents for these reactions are especially alcohols such asmethanol, ethanol, n-propanol or isopropanol, ethers such as diisopropylether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile orN,N-dimethylformamide (DMF) or mixtures of such solvents; preference isgiven to using tetrahydrofuran. The reactions are generally effectedwithin a temperature range of 0° C. to +50° C.

The protecting group PG used in compound (IV) may be a standard aminoprotecting group, for example tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Z) or (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc);preference is given to using tert-butoxycarbonyl (Boc). The detachmentof the protecting group in process step [B] (V)→(VI) is effected byknown methods. Thus, the tert-butoxycarbonyl group is typically detachedby treatment with a strong acid such as hydrogen chloride, hydrogenbromide or trifluoroacetic acid, in an inert solvent such as diethylether, 1,4-dioxane, dichloromethane or acetic acid. In the case ofbenzyloxycarbonyl as protecting group, this is preferably removed byhydrogenolysis in the presence of a suitable palladium catalyst such aspalladium on activated carbon. The (9H-fluoren-9-ylmethoxy)carbonylgroup is generally detached with the aid of a secondary amine base suchas diethylamine or piperidine [see, for example, T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999;P. J. Kocienski, Protecting Groups, 3^(rd) edition, Thieme, 2005].

Certain compounds of the formula (V), especially those in which PG istert-butoxycarbonyl, likewise have significant inhibitory activity withrespect to TASK-1 and/or TASK-3, and in this respect are alsoencompassed by the scope of definition of the present invention, i.e.the compounds of the formula (I).

The process step [B-1] (VI)+(VII)→(I-A) [amide formation] is conductedby known methods with the aid of a condensing or activating agent.Suitable agents of this kind are, for example, carbodiimides such asN,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutylchloroformate, 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds suchas 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chlorenamines suchas 1-chloro-N,N,2-trimethylprop-1-en-1-amine, 1,3,5-triazine derivativessuch as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride, phosphorus compounds such as n-propanephosphonic anhydride(PPA), diethyl cyanophosphonate, diphenylphosphoryl azide (DPPA),bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateor benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP), or uronium compounds such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), O-(1H-1-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) or2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TPTU), optionally in combination with further auxiliaries such as1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and alsoas base an alkali metal carbonate, for example sodium carbonate orpotassium carbonate, or a tertiary amine base such as triethylamine,N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine(NMP), pyridine or 4-N,N-dimethylaminopyridine (DMAP). The condensingagent or activating agent used with preference isO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in combination with N,N-diisopropylethylamineas base.

The alternative process via the carbonyl chloride (VIII)[(VI)+(VIII)→(I-A)] is generally effected in the presence of a base suchas sodium carbonate, potassium carbonate, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine (NMM), N-methylpiperidine(NMP), pyridine, 2,6-dimethylpyridine, 4-N,N-dimethylaminopyridine(DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preference is given to usingtriethylamine or N,N-diisopropylethylamine.

Suitable inert solvents for these amide-forming reactions are, forexample, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane orbis(2-methoxyethyl) ether, hydrocarbons such as benzene, toluene,xylene, pentane, hexane or cyclohexane, halohydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride,1,2-dichloroethane, trichloroethylene or chlorobenzene, or polar aproticsolvents such as acetone, methyl ethyl ketone, ethyl acetate,acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO),N,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (DMPU) orN-methylpyrrolidinone (NMP); it is also possible to use mixtures of suchsolvents. Preference is given to using dichloromethane,1,2-dichloroethane, tetrahydrofuran, N,N-dimethylformamide or mixturesof these solvents. The reactions are generally conducted within atemperature range of from −20° C. to +60° C., preferably at from 0° C.to +40° C.

The process [B-2] (VI)+(IX)→(I-B) [formation of urethanes or substitutedureas] is conducted under similar reaction conditions with regard tosolvent, addition of base and temperature as described above for theamide formation [B-1] (VI)+(VIII)→(I-A).

The reaction [B-3] (VI)+(X)→(I-C) is likewise effected in one of theabove-listed inert solvents or solvent mixtures at a temperature in therange from 0° C. to +60° C.; the addition of a base in this reaction canoptionally be dispensed with.

The amine compound (VI) can also be also be used in the process steps[B-1] (VI)+(VII) or (VIII)→(I-A), [B-2] (VI)+(IX)→(I-B) and [B-3](VI)+(X)→(I-C) in the form of a salt, for example as hydrochloride ortrifluoroacetate. In such a case, the conversion is effected in thepresence of an appropriately increased amount of the respectiveauxiliary base used.

Compounds of the formula (I) according to the invention may also beobtained by initially reducing the above-mentioned carbaldehyde of theformula (II)

in which A, D and R¹ have the meanings given above,with the aid of sodium borohydride to give an alcohol of the formula(XI)

in which A, D and R¹ have the meanings given above,subsequently converting this by treatment with methanesulfonyl chloridein the presence of a base into the corresponding mesylate of the formula(XII)

in which A, D and R¹ have the meanings given above,and then reacting the latter in the presence of a base with a compoundof the formula (III)

in which R² and the ring Q have the meanings given above,to give a compound of the formula (I).

The reduction (II)→(XI) is carried out by known methods using sodiumborohydride in an alcoholic solvent such as ethanol in a temperaturerange from 0° C. to +30° C. Subsequent conversion into the mesylate(XII) is carried out in a customary manner by treating the alcohol (XI)with methanesulfonyl chloride in the presence of a tertiary amine basesuch as, for example, triethylamine, N,N-diisopropylethylamine,N-methylmorpholine or else pyridine; the reaction is typically carriedout in a chlorinated hydrocarbon such as dichloromethane or1,2-dichloroethane as inert solvent in a temperature range from −20° C.to +20° C. For the subsequent reaction with the compound (III), themesylate (XII) is preferably not isolated beforehand but employeddirectly as crude product in a one-pot process with addition of adipolar-aprotic solvent. As such, preference is given to usingacetonitrile or N,N-dimethylformamide, and the reaction is generallycarried out in a temperature range from 0° C. to +60° C. The reaction(XII)+(III)→(I) is likewise carried out in the presence of a base;expediently—in the case of the configuration mentioned as a one-potreaction—, an appropriate excess of the amine base used beforehand forthe preparation of the mesylate may be used for this purpose.

The compounds of the formula (II) can be prepared by a process knownfrom the literature by condensing a compound of the formula (XIII)(XIII)

in which A has the meaning given above,under the influence of a base with a compound of the formula (XIV)

in which D and R¹ have the meanings given aboveandX represents a suitable leaving group, for example chlorine, bromine oriodine,to give a bicyclic system of the formula (XV)

in which A, D and R¹ have the meanings given aboveand then formylating this with a mixture of N,N-dimethylformamide andphosphorus oxychloride to give (II).

The condensation reaction (XIII)+(XIV)→(XV) is usually conducted in analcoholic solvent such as methanol, ethanol, n-propanol, isopropanol orn-butanol, in an ether such as diethyl ether, diisopropyl ether, methyltert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane orbis(2-methoxyethyl) ether, in a dipolar aprotic solvent such asN,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (DMPU) orN-methylpyrrolidinone (NMP), or else in water, at a temperature in therange from +50° C. to +150° C.; preference is given to using ethanol orwater as solvent.

Bases suitable for this reaction are in particular alkali metalbicarbonates or carbonates such as sodium bicarbonate or potassiumbicarbonate or lithium carbonate, sodium carbonate, potassium carbonateor caesium carbonate, alkali metal hydroxides such as sodium hydroxideor potassium hydroxide, or else alumina; preference is given to usingsodium bicarbonate or sodium hydroxide. Optionally—if the reactiontemperature is increased appropriately—the reaction can also be carriedout without addition of a base.

The regioselective formylation (XV)→(II) is carried out under thecustomary conditions of a Vilsmaier-Haack reaction by treating (XV) witha pre-formed mixture of N,N-dimethylformamide and phosphorus oxychloridewhich is employed in a large excess and simultaneously also serves assolvent. The reaction is generally carried out within a temperaturerange of from 0° C. to +100° C.

The processes described above can be conducted at atmospheric, elevatedor reduced pressure (for example in the range from 0.5 to 5 bar); ingeneral, the reactions are each carried out at atmospheric pressure.

Separation of the compounds of the invention into the correspondingenantiomers and/or diastereomers can, as appropriate, optionally also becarried out at the early stage of the compounds (III), (IV), (V) or(VI), which are then converted further in separated form in accordancewith the process steps described above. Such a separation ofstereoisomers can be conducted by customary methods known to the personskilled in the art. In the context of the present invention, preferenceis given to using chromatographic methods on chiral or achiralseparation phases; in the case of chiral amines as intermediates or endproducts, separation can alternatively be effected via diastereomericsalts with the aid of enantiomerically pure carboxylic acids.

Some of the compounds of the formula (IV) are commercially available, orthey are described as such in the literature, or they can be preparedfrom other commercially available compounds analogously to methods knownfrom the literature. One such preparation is shown in an exemplarymanner in Reaction Schemes 1-3 below and then in each case explained ingreater detail:

Here, starting with 2,5-dihydrofuran (1), initially dialdehyde (2) wasobtained by ozonolysis at −78° C. in dichloromethane as solvent, whichwas directly, as crude product without any further purification, takenup in water and treated with dicarboxylic acid (3) and sodium acetate.After subsequent addition of benzylamine (4) in 3 N hydrochloric acid,the resulting mixture was stirred at room temperature for 16 h, and thebicyclic aminoketone (5) was then isolated in a yield of 16%. In anethanol/water mixture, ketone (5) was then converted in a yield of 87%into the oxime (6) as an E/Z mixture, by reacting with hydroxylaminehydrochloride and sodium acetate at 70°-80° C. for three hours. Reactionwith sodium carbonate and tosyl chloride in an acetonitrile/watermixture at a temperature of 70°-80° C. over 15 h gave the ring-extendedproduct, the seven-membered lactam (7), in a yield of 71%. This lactam(7) was then, by reduction with lithium aluminium hydride in THF at atemperature of 20°-30° C. and a reaction time of 16 h, converted intothe bridged diamine (8), which was reacted as a crude product withdi-tert-butyl dicarbonate and triethylamine in dichloromethane over 5 hat 20°-30° C. The resulting doubly protected diamine (9) was, afterwork-up and chromatographic purification, obtained in a yield of 82%.The final hydrogenation with palladium hydroxide as catalyst in methanolat a temperature of 20°-30° C. and a hydrogen pressure of 50 Psi (about3.45 bar) over 4 h then gave the desired target compound, themonoprotected diamine (10), in a yield of 69% after chromatographicpurification.

Here, initially cyclohex-2-en-1-one (11), 4-methoxyaniline (12) andformaldehyd were reacted with one another in the presence of DL-prolinein a 3-component reaction. After a reaction time of 30 h at 50° C. inDMSO as solvent, the bicyclic aminoketone (13) was obtained in racemicform with a yield of 18% [cf. L. Eriksson et al., Angew. Chem. Int. Ed.44, 4877 (2005)]. By reaction with hydroxylamine hydrochloride andsodium carbonate in THF at room temperature, ketone (13) was thenconverted into the E/Z oxime (14), which was subsequently treated withpolyphosphoric acid in toluene at 100° C. for 5 h. After work-up of thereaction, the ring-extended product, i.e. the bicyclic lactam (15), wasisolated in a yield of 39%. Subsequent oxidative removal of the anisolegroup with the aid of cerium(IV) ammonium nitrate in anacetonitrile/water mixture at room temperature afforded the aminolactam(16), which was directly, as an aqueous crude product solution, reactedfurther with benzyloxycarbonyl chloride (benzyl carbonochloridate) inthe presence of sodium carbonate (pH 10). Chromatographic purificationgave the Cbz protected derivative (17) in a total yield of 48% over thelast two steps. Via reduction of the lactam (17) using borane/dimethylsulfide complex in THF at 65° C., it was possible to obtain the amine(18), which for its part was directly reacted further as an aqueouscrude product solution in the presence of sodium carbonate (pH 10) withdi-tert-butyl dicarbonate, giving, in a total yield of 63% over the lasttwo steps, the doubly protected diamine (19). The racemic compoundobtained in this manner was then separated into the enantiomers (19a)and (19b) (in each case with >98% ee) by SFC-HPLC on a chiral phase.Removal of the Cbz protective group by hydrogenolysis (1 bar ofhydrogen, 10% palladium on carbon as catalyst) in methanol finally gavethe desired target compounds, i.e. the monoprotected diamines (20a) and(20b), in enantiomerically pure form.

Here, initially the bicyclic aminoketone (21) was converted by reactionwith hydroxylamine hydrochloride and diisopropylethylamine in ethanol ata temperature of 35° C. over 2 h into the E/Z oxime (22) (yield 84%).Oxime (22) was then treated with polyphosphoric acid in toluene at110°-120° C. for 2 h. After work-up of the reaction, the ring-extendedproduct, i.e. the bicyclic lactam (23), was isolated in a yield of 49%.Subsequent reduction with sodium bis(2-methoxyethoxy)aluminiumhydride(Red-Al®) in THF at a temperature of 50° C. for 3 h gave the diamine(24), which was subsequently converted by reaction withbenzyloxycarbonyl chloride (benzyl carbonochloridate) and triethylaminein dichloromethane at 0°-10° C. into the Cbz-protected derivative (25).Reaction of compound (25) with 1-chloroethyl carbonochloridate (26) in1,2-dichloroethane at 85° C. for 5 h, addition of methanol and furtherheating at 85° C. for 1 h gave the N-debenzylated compound (27). Thiswas subsequently reacted in dichloromethane with di-tert-butyldicarbonate in the presence of triethylamine and4-N,N-dimethylaminopyridine; after a reaction time of 2 h at 10° C., thedoubly protected diamine (28) was isolated in a yield of 69%. Theracemic compound obtained in this manner was then separated into theenantiomers (28a) and (28b) (in each case with >95.5% ee) by SFC-HPLC ona chiral phase. Removal of the Cbz protective group by hydrogenolysis (1atm of hydrogen, 10% palladium on carbon as catalyst) in methanolfinally gave the desired target compounds, i.e. the monoprotecteddiamines (29a) and (29b), in enantiomerically pure form.

The compounds of the formulae (III), (VII), (VIII), (IX), (X), (XIII)and (XIV) are either commercially available or described as such in theliterature, or they can be prepared in a simple manner from othercommercially available compounds by methods familiar to the personskilled in the art and known from the literature. Numerous detailedprocedures and further literature references can also be found in theexperimental section, in the section on the preparation of the startingcompounds and intermediates.

The preparation of the compounds according to the invention can beillustrated further in an exemplary manner by the Reaction Schemes 4-7below:

The compounds of the invention have valuable pharmacological propertiesand can be used for prevention and treatment of diseases in humans andanimals.

The compounds of the invention are potent and selective blockers ofTASK-1 and in particular TASK-3 channels and are therefore suitable forthe treatment and/or prevention of disorders and pathological processes,in particular those caused by activation of TASK-1 and/or TASK-3 or byactivated TASK-1 and/or TASK-3, and of disorders secondary to damagecaused by TASK-1 and/or TASK-3.

For the purposes of the present invention, this includes in particulardisorders from the group of the respiratory disorders and sleep-relatedrespiratory disorders, such as obstructive sleep apnoea (in adults andchildren), primary snoring, obstructive snoring (upper airway resistancesyndrome, heavy snoring, hypopnoea syndrome), central sleep apnoea,mixed sleep apnoea, Cheyne-Stokes respiration, primary sleep apnoea ofinfancy, apparent life-threatening event, central sleep apnoea as aresult of the use of medicaments or the use of other substances, obesityhypoventilation syndrome, disrupted central respiratory drive, suddeninfant death, primary alveolar hypoventilation syndrome, postoperativehypoxia and apnoea, muscular respiratory disorders, respiratorydisorders following long-term ventilation, respiratory disorders duringadaptation in high mountains, acute and chronic pulmonary diseases withhypoxia and hypercapnia, sleep-related non-obstructive alveolarhypoventilation and the congenital central alveolar hypoventilationsyndrome.

The compounds of the invention can additionally be used for treatmentand/or prevention of neurodegenerative disorders such as dementia,dementia with Lewy bodies, Alzheimer's disease, Parkinson's disease,Huntington's disease, Pick's disease, Wilson's disease, progressivesupranuclear paresis, corticobasal degeneration, tauopathy,frontotemporal dementia and parkinsonism linked to chromosome 17,multisystem atrophy, spinocerebellar ataxias, spinobulbar muscularatrophy of the Kennedy type, Friedreich's ataxia,dentatorubral-pallidoluysian atrophy, amyotrophic lateral sclerosis,primary lateral sclerosis, spinal muscular atrophy, Creutzfeldt-Jakobdisease and variants of Creutzfeldt-Jakob disease, infantile neuroaxonaldystrophy, neurodegeneration with brain iron accumulation,frontotemporal lobar degeneration with ubiquitin proteasome system andfamilial encephalopathy with neuroserpin inclusions.

In addition, the compounds of the invention can be used for treatmentand/or prevention of neuroinflammatory and neuroimmunological disordersof the central nervous system (CNS), for example multiple sclerosis(Encephalomyelitis disseminata), transverse myelitis, Neuromyelitisoptica, acute disseminated encephalomyelitis, optic neuritis,meningitis, encephalitis, demyelinating diseases and also inflammatoryvascular changes in the central nervous system.

Moreover, the compounds of the invention are suitable for the treatmentand/or prevention of neoplastic disorders such as, for example, skincancer, breast cancer, lung cancer, colon cancer and prostate cancer.

The compounds of the invention are also suitable for treatment and/orprevention of cardiac arrhythmias, for example atrial and ventriculararrhythmias, conduction defects such as first- to third-degreeatrio-ventricular blocks, supraventricular tachyarrhythmia, atrialfibrillation, atrial flutter, ventricular fibrillation, ventricularflutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia,atrial and ventricular extrasystoles, AV-junctional extrasystoles, sicksinus syndrome, syncopes and AV nodal re-entrant tachycardia.

Further cardiovascular disorders where the compounds of the inventioncan be employed for treatment and/or prevention are, for example, heartfailure, coronary heart disease, stable and unstable angina pectoris,high blood pressure (hypertension), pulmonary-arterial hypertension(PAH) and other forms of pulmonary hypertension (PH), renalhypertension, peripheral and cardial vascular disorders,Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS),autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis,aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock suchas cardiogenic shock, septic shock and anaphylactic shock, furthermorethromboembolic disorders and ischaemias such as myocardial ischaemia,myocardial infarction, stroke, cardiac hypertrophy, transient andischaemic attacks, preeclampsia, inflammatory cardiovascular disorders,spasms of the coronary arteries and peripheral arteries, oedemaformation such as, for example, pulmonary oedema, cerebral oedema, renaloedema or oedema caused by heart failure, peripheral circulatorydisturbances, reperfusion damage, arterial and venous thromboses,microalbuminuria, myocardial insufficiency, endothelial dysfunction,micro- and macrovascular damage (vasculitis), and also to preventrestenoses, for example after thrombolysis therapies, percutaneoustransluminal angioplasties (PTA), percutaneous transluminal coronaryangioplasties (PTCA), heart transplants and bypass operations.

In the context of the present invention, the term “heart failure”encompasses both acute and chronic forms of heart failure, and alsospecific or related disease types thereof, such as acute decompensatedheart failure, right heart failure, left heart failure, global failure,ischaemic cardiomyopathy, dilatative cardiomyopathy, hypertrophiccardiomyopathy, idiopathic cardiomyopathy, congenital heart defects,heart valve defects, heart failure associated with heart valve defects,mitral valve stenosis, mitral valve insufficiency, aortic valvestenosis, aortic valve insufficiency, tricuspid valve stenosis,tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valveinsufficiency, combined heart valve defects, myocardial inflammation(myocarditis), chronic myocarditis, acute myocarditis, viralmyocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiacstorage disorders and diastolic and systolic heart failure.

The compounds of the invention can additionally be used for treatmentand/or prevention of asthmatic disorders of varying severity withintermittent or persistent characteristics (refractive asthma, bronchialasthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament-or dust-induced asthma), of various forms of bronchitis (chronicbronchitis, infectious bronchitis, eosinophilic bronchitis), ofbronchiectasis, pneumonia, farmer's lung and related disorders, coughsand colds (chronic inflammatory cough, iatrogenic cough), inflammationof the nasal mucosa (including medicament-related rhinitis, vasomotoricrhinitis and seasonal allergic rhinitis, for example hay fever) and ofpolyps.

The compounds of the invention are also suitable for treatment and/orprevention of renal disorders, in particular renal insufficiency andkidney failure. In the context of the present invention, the terms“renal insufficiency” and “kidney failure” encompass both acute andchronic manifestations thereof and also underlying or related renaldisorders such as renal hypoperfusion, intradialytic hypotension,obstructive uropathy, glomerulopathies, glomerulonephritis, acuteglomerulonephritis, glomerulosclerosis, tubulointerstitial diseases,nephropathic disorders such as primary and congenital kidney disease,nephritis, immunological kidney disorders such as kidney transplantrejection and immunocomplex-induced kidney disorders, nephropathyinduced by toxic substances, nephropathy induced by contrast agents,diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts,nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndromewhich can be characterized diagnostically, for example by abnormallyreduced creatinine and/or water excretion, abnormally elevated bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes, for example glutamyl synthetase, alteredurine osmolarity or urine volume, elevated microalbuminuria,macroalbuminuria, lesions on glomerulae and arterioles, tubulardilatation, hyperphosphatemia and/or need for dialysis. The presentinvention also encompasses the use of the compounds of the invention fortreatment and/or prevention of sequelae of renal insufficiency, forexample hypertension, pulmonary oedema, heart failure, uraemia, anaemia,electrolyte disturbances (for example hyperkalaemia, hyponatraemia) anddisturbances in bone and carbohydrate metabolism.

In addition, the compounds of the invention are suitable for treatmentand/or prevention of disorders of the urogenital system, for examplebenign prostate syndrome (BPS), benign prostate hyperplasia (BPH),benign prostate enlargement (BPE), bladder outlet obstruction (BOO),lower urinary tract syndromes (LUTS), neurogenic overactive bladder(OAB), incontinence, for example mixed urinary incontinence, urgeurinary incontinence, stress urinary incontinence or overflow urinaryincontinence (MUI, UUI, SUI, OUI), pelvic pain, and also erectiledysfunction and female sexual dysfunction.

The compounds of the invention are further suitable for treatment and/orprevention of inflammatory disorders and autoimmune disorders such as,for example, rheumatoid disorders, inflammatory eye disorders, chronicobstructive pulmonary disease (COPD), acute respiratory distresssyndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency(AATD), pulmonary emphysema (e.g. pulmonary emphysema induced bycigarette smoke), cystic fibrosis (CF), sepsis (SIRS), multiple organfailure (MODS, MOF), inflammatory disorders of the kidney, chronicintestinal inflammations (IBD, Crohn's disease, ulcerative colitis),pancreatitis, peritonitis, cystitis, urethritis, prostatitis,epidimytitis, oophoritis, salpingitis and vulvovaginitis, and also forthe treatment and/or prevention of fibrotic disorders of internal organssuch as, for example, the lung, the heart, the kidney, the bone marrowand especially the liver, of dermatological fibroses and of fibroticdisorders of the eye. In the context of the present invention, the term“fibrotic disorders” includes in particular disorders such as hepaticfibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardialfibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis,fibrotic damage resulting from diabetes, bone marrow fibrosis,peritoneal fibrosis and similar fibrotic disorders, scleroderma,morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy,proliferative vitroretinopathy and disorders of the connective tissue(for example sarcoidosis). The compounds of the invention can likewisebe used for promotion of wound healing, for controlling postoperativescarring, for example following glaucoma operations and cosmetically forageing or keratinized skin.

In addition, the compounds of the invention can be used for treatmentand/or prevention of arteriosclerosis, impaired lipid metabolism anddyslipidemias (hypolipoproteinaemia, hypertriglyceridaemias,hyperlipidaemia, combined hyperlipidaemias, hypercholesterolaemia,abetalipoproteinaemia, sitosterolaemia), xanthomatosis, Tangier disease,adiposity, obesity, metabolic disorders (metabolic syndrome,hyperglycaemia, insulin-dependent diabetes, non-insulin-dependentdiabetes, gestation diabetes, hyperinsulinaemia, insulin resistance,glucose intolerance and diabetic sequelae, such as retinopathy,nephropathy and neuropathy), of anaemias such as hemolytic anaemias, inparticular haemoglobinopathies such as sickle cell anaemia andthalassaemias, megaloblastic anaemias, iron deficiency anaemias,anaemias owing to acute blood loss, displacement anaemias and aplasticanaemias, of disorders of the gastrointestinal tract and the abdomen(glossitis, gingivitis, periodontitis, esophagitis, eosinophilicgastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, anuspruritis, diarrhea, coeliac disease, hepatitis, hepatic fibrosis,cirrhosis of the liver, pancreatitis and cholecystitis), of disorders ofthe central nervous system (stroke, epilepsy, depression), immunedisorders, thyroid disorders (hyperthyreosis), skin disorders(psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis,keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupuserythematosus, erythema, lymphomas, skin cancer, Sweet syndrome,Weber-Christian syndrome, scar formation, wart formation, chilblains),of inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis,iritis, uveitis, chorioiditis, ophthalmitis), of viral diseases (causedby influenza, adeno and corona viruses, for example HPV, HCMV, HIV,SARS), of disorders of the skeletal bone and the joints and also theskeletal muscle (various forms of arthritis, for example endarteritis,mesarteritis, periarteritis, panarteritis, arteritis rheumatica,arteritis deformans, arteritis temporalis, arteritis cranialis,arteritis gigantocellularis and arteritis granulomatosa, and also Hortonsyndrome, Churg-Strauss syndrome and Takayasu arteritis), of Muckle-Wellsyndrome, of Kikuchi disease, of polychondritis, dermatosclerosis andalso other disorders having an inflammatory or immunological component,for example cataract, cachexia, osteoporosis, gout, incontinence,leprosy, Sezary syndrome and paraneoplastic syndrome, in the event ofrejection reactions after organ transplants and for wound healing andangiogenesis particularly in the case of chronic wounds.

By virtue of their property profile, the compounds of the invention arepreferably suitable for treatment and/or prevention of respiratorydisorders, in particular of sleep-related respiratory disorders such asobstructive and central sleep apnoea and also primary and obstructivesnoring, for treatment and/or prevention of cardiac arrhythmias and alsofor treatment and/or prevention of neurodegenerative, neuroinflammatoryand neuroimmunological disorders.

The aforementioned well-characterized diseases in humans can also occurwith comparable etiology in other mammals and can likewise be treatedtherein with the compounds of the present invention.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” and “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or advancement of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

The present invention thus further provides for the use of the compoundsof the invention for treatment and/or prevention of disorders,especially of the aforementioned disorders.

The present invention further provides for the use of the compounds ofthe invention for production of a medicament for treatment and/orprevention of disorders, especially of the aforementioned disorders.

The present invention further provides a medicament comprising at leastone of the compounds of the invention for treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The present invention further provides for the use of the compounds ofthe invention in a method for treatment and/or prevention of disorders,especially of the aforementioned disorders.

The present invention further provides a process for treatment and/orprevention of disorders, especially of the aforementioned disorders,using an effective amount of at least one of the compounds of theinvention.

The compounds of the invention can be used alone or, if required, incombination with one or more other pharmacologically active substances,provided that this combination does not lead to undesirable andunacceptable side effects. The present invention therefore furtherprovides medicaments comprising at least one of the compounds of theinvention and one or more further drugs, especially for treatment and/orprevention of the aforementioned disorders. Preferred examples ofcombination active ingredients suitable for this purpose include:

-   -   respiratory stimulants, by way of example and with preference        theophylline, doxapram, nikethamide or caffeine;    -   psychostimulants, by way of example and with preference        modafinil or armodafinil;    -   amphetamines and amphetamine derivatives, by way of example and        with preference amphetamine, metamphetamine or methylphenidate;    -   serotonin reuptake inhibitors, by way of example and with        preference fluoxetine, paroxetine, citalopram, escitalopram,        sertraline, fluvoxamine or trazodone;    -   serotonin precursors, by way of example and with preference        L-tryptophan;    -   selective serotonin noradrenaline reuptake inhibitors, by way of        example and with preference venlafaxine or duloxetine;    -   noradrenergic and specific serotonergic antidepressants, by way        of example and with preference mirtazapine;    -   selective noradrenaline reuptake inhibitors, by way of example        and with preference reboxetine;    -   tricyclic antidepressants, by way of example and with preference        amitriptyline, protriptyline, doxepine, trimipramine,        imipramine, clomipramine or desipramine;    -   alpha2-adrenergic agonists, by way of example and with        preference clonidine;    -   GABA agonists, by way of example and with preference baclofen;    -   alpha sympathomimetics, by way of example and with preference        xylometazoline, oxymetazoline, phenylephrine, naphazoline,        tetryzoline or tramazoline;    -   glucocorticoids, by way of example and with preference        fluticasone, budesonide, beclometasone, mometasone, tixocortol        or triamcinolone;    -   cannabinoid receptor agonists;    -   carboanhydrase inhibitors, by way of example and with preference        acetazolamide, methazolamide or diclofenamide;    -   opioid and benzodiazepine receptor antagonists, by way of        example and with preference flumazenil, naloxone or naltrexone;    -   cholinesterase inhibitors, by way of example and with preference        neostigmine, pyridostigmine, physostigmine, donepezil,        galantamine or rivastigmine;    -   N-methyl-D-aspartate and glutamate antagonists, by way of        example and with preference amantadine, memantine or sabeluzole;    -   nicotine receptor agonists;    -   leukotriene receptor antagonists, by way of example and with        preference montelukast or tipelukast;    -   dopamine receptor antagonists, by way of example and with        preference dromperidone, metoclopramide or benzamide,        butyrophenone or phenothiazine derivatives;    -   appetite suppressants, by way of example and with preference        sibutramine, topiramate, phentermine, lipase inhibitors or        cannabinoid receptor antagonists;    -   proton pump inhibitors, by way of example and with preference        pantoprazole, omeprazole, esomeprazole, lansoprazole or        rabeprazole;    -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2,        3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil,        vardenafil, tadalafil, udenafil, dasantafil, avanafil,        mirodenafil or lodenafil;    -   NO- and heme-independent activators of soluble guanylate cyclase        (sGC), such as in particular the compounds described in WO        01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462        and WO 02/070510;    -   NO-independent but haem-dependent stimulators of soluble        guanylate cyclase (sGC), such as in particular riociguat,        vericiguat and the compounds described in WO 00/06568, WO        00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO        2012/004258, WO 2012/028647 and WO 2012/059549;    -   prostacyclin analogs and IP receptor agonists, by way of example        and with preference iloprost, beraprost, treprostinil,        epoprostenol or selexipag;    -   edothelin receptor antagonists, by way of example and with        preference bosentan, darusentan, ambrisentan or sitaxsentan;    -   compounds which inhibit human neutrophile elastase (HNE), by way        of example and with preference sivelestat or DX-890 (reltran);    -   compounds which inhibit the degradation and alteration of the        extracellular matrix, by way of example and with preference        inhibitors of the matrix metalloproteases (MMPs), especially        inhibitors of stromelysin, collagenases, gelatinases and        aggrecanases (in this context particularly of MMP-1, MMP-3,        MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase        (MMP-12);    -   compounds which block the binding of serotonin to its receptors,        by way of example and with preference antagonists of the        5-HT_(2B) receptor such as PRX-08066;    -   antagonists of growth factors, cytokines and chemokines, by way        of example and with preference antagonists of TGF-β, CTGF, IL-1,        IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;    -   Rho kinase-inhibiting compounds, by way of example and with        preference fasudil, Y-27632, SLx-2119, BF-66851, BF-66852,        BF-66853, KI-23095 or BA-1049;    -   compounds which influence the energy metabolism of the heart, by        way of example and with preference etomoxir, dichloroacetate,        ranolazine or trimetazidine;    -   compounds which inhibit the signal transduction cascade, by way        of example and with preference from the group of the kinase        inhibitors, in particular from the group of the tyrosine kinase        and/or serine/threonine kinase inhibitors, by way of example and        with preference nintedanib, dasatinib, nilotinib, bosutinib,        regorafenib, sorafenib, sunitinib, cediranib, axitinib,        telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib,        erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib,        semaxanib or tandutinib;    -   anti-obstructive agents as used, for example, for treatment of        chronic obstructive pulmonary disease (COPD) or bronchial        asthma, by way of example and with preference from the group of        the inhalatively or systemically administered agonists of the        beta-adrenergic receptor (beta-mimetics) and the inhalatively        administered antimuscarinergic substances;    -   antiinflammatory, immunomodulating, immunosuppressive and/or        cytotoxic agents, by way of example and with preference from the        group of the systemically or inhalatively administered        corticosteroids and also dimethyl fumarate, fingolimod,        glatiramer acetate, β-interferons, natalizumab, teriflunomide,        mitoxantrone, immunoglobulins, acetylcysteine, montelukast,        tipelukast, azathioprine, cyclophosphamide, hydroxycarbamide,        azithromycin, interferon-γ, pirfenidone or etanercept;    -   antifibrotic agents, by way of example and with preference        lysophosphatidic acid receptor 1 (LPA-1) antagonists, CTGF        inhibitors, IL-4 antagonists, IL-13 antagonists, TGF-β        antagonists or pirfenidone;    -   antithrombotic agents, by way of example and with preference        from the group of platelet aggregation inhibitors, the        anticoagulants and the profibrinolytic substances;    -   hypotensive active ingredients, by way of example and with        preference from the group of the calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, vasopeptidase        inhibitors, endothelin antagonists, renin inhibitors, alpha        receptor blockers, beta receptor blockers, mineralocorticoid        receptor antagonists and also the diuretics; and/or    -   active ingredients altering lipid metabolism, for example and        with preference from the group of the thyroid receptor agonists,        cholesterol synthesis inhibitors such as, by way of example and        preferably, HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, the ACAT inhibitors, CETP inhibitors, MTP        inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,        cholesterol absorption inhibitors, lipase inhibitors, polymeric        bile acid adsorbents, bile acid reabsorption inhibitors and        lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a beta-adrenergicreceptor agonist, by way of example and with preference albuterol,isoproterenol, metaproterenol, terbutalin, fenoterol, formoterol,reproterol, salbutamol or salmeterol.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an antimuscarinergicsubstance, by way of example and with preference ipratropium bromide,tiotropium bromide or oxitropium bromide.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a corticosteroid, by wayof example and with preference prednisone, prednisolone,methylprednisolone, triamcinolone, dexamethasone, betamethasone,beclomethasone, flunisolide, budesonide or fluticasone.

Antithrombotic agents are preferably understood to mean compounds fromthe group of the platelet aggregation inhibitors, the anticoagulants andthe profibrinolytic substances.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a platelet aggregationinhibitor, by way of example and with preference aspirin, clopidogrel,ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a thrombin inhibitor, byway of example and with preference ximelagatran, melagatran, dabigatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a GPIIb/IIIa antagonist,by way of example and with preference tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a factor Xa inhibitor, byway of example and with preference rivaroxaban, apixaban, fidexaban,razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150,KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803,SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a vitamin K antagonist,by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of the calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, and the diuretics.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a calcium antagonist, byway of example and with preference nifedipine, amlodipine, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an alpha-1-receptorblocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a beta-receptor blocker,by way of example and with preference propranolol, atenolol, timolol,pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol,nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol,celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol,adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an angiotensin AII antagonist,preferred examples being losartan, candesartan, valsartan, telmisartanor embusartan.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an ACE inhibitor, by wayof example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an endothelin antagonist,by way of example and with preference bosentan, darusentan, ambrisentanor sitaxsentan.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a renin inhibitor, by wayof example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a mineralocorticoidreceptor antagonist, by way of example and with preferencespironolactone, eplerenone or finerenone.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a diuretic, by way ofexample and with preference furosemide, bumetanide, torsemide,bendroflumethiazide, chlorothiazide, hydrochlorothiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide,chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol,amiloride or triamterene.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbers, bile acidreabsorption inhibitors, lipase inhibitors and the lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a CETP inhibitor, by wayof example and with preference torcetrapib (CP-529 414), JJT-705 or CETPvaccine (Avant).

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins, by way of example and withpreference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a squalene synthesisinhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an ACAT inhibitor, by wayof example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an MTP inhibitor, by wayof example and with preference implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a PPAR-gamma agonist, byway of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a PPAR-delta agonist, byway of example and with preference GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a cholesterol absorptioninhibitor, by way of example and with preference ezetimibe, tiqueside orpamaqueside.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a lipase inhibitor, byway of example and with preference orlistat.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a polymeric bile acidadsorber, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a bile acid reabsorptioninhibitor, by way of example and with preference ASBT (=IBAT)inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 orSC-635.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

Particular preference is given to combinations of the compounds of theinvention with one or more further active ingredients selected from thegroup consisting of respiratory stimulants, psychostimulants, serotoninreuptake inhibitors, noradrenergic, serotonergic and tricyclicantidepressants, sGC stimulators, mineralocorticoid receptorantagonists, antiinflammatory drugs, immunomodulators,immunosuppressives and cytotoxic drugs.

If required, the substances of the invention can also be employed inconjunction with the use of one or more medical technical devices orauxiliaries, provided that this does not lead to unwanted andunacceptable side-effects. Medical devices and auxiliaries suitable forsuch a combined application are, by way of example and with preference:

-   -   devices for positive airway pressure ventilation, by way of        example and with preference CPAP (continuous positive airway        pressure) devices, BiPAP (bilevel positive airway pressure)        devices and IPPV (intermittent positive pressure ventilation)        devices;    -   neurostimulators of the Nervus hypoglossus;    -   intraoral auxiliaries, by way of example and with preference        protrusion braces;    -   nasal disposable valves;    -   nasal stents.

The present invention further provides medicaments which comprise atleast one compound of the invention, typically together with one or moreinert, non-toxic, pharmaceutically suitable excipients, and for the usethereof for the aforementioned purposes.

The compounds of the invention can act systemically and/or locally. Forthis purpose, they can be administered in a suitable manner, for exampleby the oral, parenteral, pulmonal, intrapulmonal (inhalative), nasal,intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal,transdermal, conjunctival or otic route, or as an implant or stent.

The compounds of the invention can be administered in administrationforms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the compounds of theinvention rapidly and/or in a modified manner and which contain thecompounds of the invention in crystalline and/or amorphized and/ordissolved form, for example tablets (uncoated or coated tablets, forexample with gastric juice-resistant or retarded-dissolution orinsoluble coatings which control the release of the compound of theinvention), tablets or films/oblates which disintegrate rapidly in theoral cavity, films/lyophilizates, capsules (for example hard or softgelatin capsules), sugar-coated tablets, granules, pellets, powders,emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass an absorption step (e.g. take placeintravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. take place inhalatively,intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Administration forms suitable for parenteraladministration include preparations for injection and infusion in theform of solutions, suspensions, emulsions, lyophilizates or sterilepowders.

Suitable for the other administration routes are, for example,pharmaceutical forms for inhalation (including powder inhalers,nebulizers, metered aerosols), nasal drops, solutions or sprays, throatsprays, tablets for lingual, sublingual or buccal administration,films/wafers or capsules, suppositories, eye drops, eye ointments oreyewashes, ocular inserts, ear drops, sprays, powders, washes ortampons, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, emulsions, microemulsions, ointments,creams, transdermal therapeutic systems (e.g. patches), milk, pastes,foams, dusting powders, implants or stents.

Preference is given to oral, intravenous, intranasal and pharyngealadministration.

In one embodiment, administration is by the intranasal route. In oneembodiment, intranasal administration is effected with the eye of eyedrops or a nasal spray. In one embodiment, intranasal administration iseffected with the eye of a nasal spray.

The compounds of the invention can be converted to the administrationforms mentioned. This can be done in a manner known per se, by mixingwith inert, nontoxic, pharmaceutically suitable excipients. Theseexcipients include

-   -   fillers and carriers (for example cellulose, microcrystalline        cellulose, for example Avicel®, lactose, mannitol, starch,        calcium phosphates, for example Di-Cafos®),    -   ointment bases (for example vaseline, paraffins, triglycerides,        waxes, wool wax, wool wax alcohols, lanolin, hydrophilic        ointment, polyethylene glycols),    -   suppository bases (for example polyethylene glycols, cocoa        butter, hard fat),    -   solvents (e.g. water, ethanol, isopropanol, glycerol, propylene        glycol, mid-chain triglycerides fatty oils, liquid polyethylene        glycols, paraffins),    -   surfactants, emulsifiers, dispersants or wetting agents (for        example sodium dodecylsulfate, lecithin, phospholipids, fatty        alcohols, for example Lanette®, sorbitan fatty acid esters, for        example Span®, polyoxyethylene sorbitan fatty acid esters, for        example Tween®, polyoxyethylene fatty acid glycerides, for        example Cremophor®, polyoxyethylene fatty acid esters,        polyoxyethylene fatty alcohol ethers, glycerol fatty acid        esters, poloxamers, for example Pluronic®),    -   buffer substances, and also acids and bases (for example        phosphates, carbonates, citric acid, acetic acid, hydrochloric        acid, sodium hydroxide, ammonium carbonate, trometamol,        triethanolamine),    -   isotonizing agents (for example glucose, sodium chloride),    -   adsorbents (for example finely divided silicas),    -   viscosity-increasing agents, gel formers, thickeners or binders        (for example polyvinylpyrrolidone, methyl cellulose,        hydroxypropyl cellulose, hydroxypropyl methylcellulose,        carboxymethyl cellulose-sodium, starch, carbomers, polyacrylic        acids, for example Carbopol®, alginates, gelatins),    -   disintegrants (for example modified starch, carboxymethyl        cellulose-sodium, sodium starch glycolate, for example        Explotab®, crosslinked polyvinylpyrrolidone,        croscarmellose-sodium, for example AcDiSol®),    -   flow regulators, lubricants, glidants and mould release agents        (for example magnesium stearate, stearic acid, talc, finely        divided silicas, for example Aerosil®),    -   coating agents (for example sugar, shellac) and film formers for        films or diffusion membranes with fast or modified dissolution        (for example polyvinylpyrrolidones, for example Kollidon®,        polyvinyl alcohol, ethyl cellulose, hydroxypropyl cellulose,        hydroxypropy methyl cellulose, hydroxypropyl methyl cellulose        phthalate, cellulose acetate, cellulose acetate phthalate,        polyacrylates, polymethacrylates, for example Eudragit®),    -   capsule materials (e.g. gelatins, hydroxypropyl methyl        cellulose),    -   natural polymers (for example albumins);    -   synthetic polymers (for example polylactides, polyglycolides,        polyacrylates, polymethacrylates, for example Eudragit®,        polyvinylpyrrolidones, for example Kollidon®, polyvinyl        alcohols, polyvinyl acetates, polyethylene oxides, polyethylene        glycols and the copolymers and block copolymers thereof),    -   plasticizers (for example polyethylene glycols, propylene        glycol, glycerol, triacetin, triacetyl citrate, dibutyl        phthalate),    -   penetrants;    -   stabilizers (e.g. antioxidants, for example ascorbic acid,        sodium ascorbate, ascorbyl palmitate, butylhydroxyanisole,        butylhydroxytoluene, propyl gallate),    -   preservatives (for example parabens, sorbic acid, sodium        benzoate, thiomersal, benzalkonium chloride, chlorhexidine        acetate);    -   dyes (e.g. inorganic pigments, for example iron oxides, titanium        dioxide),    -   aromas, sweeteners, flavour and/or odour correctors.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of active compound ofabout 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of bodyweight to achieve effective results. In the case of oral administrationthe dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kgand most preferably 0.1 to 10 mg/kg of body weight. In the case ofintrapulmonary administration, the amount of active compound isgenerally about 0.1 to 50 mg per inhalation.

In one embodiment, the dosage in the case of intranasal administrationis about 0.1 μg to 500 μg per day. In a further embodiment, the dosagein the case of intranasal administration is about 1 μg to 250 μg perday. In a further embodiment, the dosage in the case of intranasaladministration is about 1 μg to 120 μg per day. In a further embodiment,the dose of about 0.1 μg to 500 μg per day, or of about 1 μg to 250 μgper day, or of about 1 μg to 120 μg per day, is administered once dailyby the intranasal route before sleeping. In one embodiment, the dose ofabout 0.1 μg to 500 μg per day, or of about 1 μg to 250 μg per day, orof about 1 μg to 120 μg per day, is administered once daily with half toeach nostril. In one embodiment, the dose of about 0.1 μg to 500 μg perday, or of about 1 μg to 250 μg per day, or of about 1 μg to 120 μg perday, is administered once daily with half to each nostril beforesleeping.

It may nevertheless be necessary in some cases to deviate from thestated amounts of active compounds, specifically as a function of bodyweight, route of administration, individual response to the activeingredient, nature of the preparation and time or interval over whichadministration takes place. Thus in some cases it may be sufficient tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case ofadministration of greater amounts, it may be advisable to divide theminto several individual doses over the day.

The working examples which follow illustrate the invention. Theinvention is not restricted to the examples.

A. EXAMPLES Abbreviations and Acronyms

abs. absolute

Ac acetyl

aq. aqueous, aqueous solution

Boc tert-butoxycarbonyl

br. broad (in NMR signal)

Ex. Example

Bu butyl

c Concentration

CAN cerium(IV) ammonium nitrate

cat. catalytic

Cbz benzyloxycarbonyl

CI chemical ionization (in MS)

d doublet (in NMR)

d day(s)

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

dd doublet of doublets (in NMR)

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

dq doublet of quartets (in NMR)

dt doublet of triplets (in NMR)

EI electron impact ionization (in MS)

eq. equivalent(s)

ESI electrospray ionization (in MS)

Et ethyl

h hour(s)

HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HOBt 1-hydroxy-1H-benzotriazole hydrate

HPLC high-pressure, high-performance liquid chromatography

iPr isopropyl

conc. concentrated (in the case of a solution)

LC liquid chromatography

LC-MS liquid chromatography-coupled mass spectrometry

lit. literature (reference)

m multiplet (in NMR)

Me methyl

min minute(s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

Pd/C palladium on activated charcoal

Ph phenyl

PPS Polyphosphoric acid

Pr propyl

q quartet (in NMR)

quant. quantitative (in chemical yield)

Red-Al® sodium bis(2-methoxyethoxy)aluminiumhydride

R_(f) retention index (in TLC)

RP reverse phase (in HPLC)

R_(t) retention time (in HPLC, LC-MS)

RT room temperature

s singlet (in NMR)

SFC supercritical liquid chromatography

t triplet (in NMR)

tBu tert-butyl

TFA trifluoroacetic acid

THF tetrahydrofuran

Ts tosyl (p-toluenesulfonyl)

UV ultraviolet spectrometry

v/v volume to volume ratio (of a solution)

LC-MS and HPLC Methods:

Method 1 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8 μm, 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;temperature: 50° C.; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

Method 2 (LC-MS):

MS instrument: Thermo Scientific FT-MS; instrument type UHPLC: ThermoScientific UltiMate 3000; column: Waters HSS T3 C18 1.8 μm, 75 mm×2.1mm; mobile phase A: 1 l of water+0.01% formic acid, mobile phase B: 1 lof acetonitrile+0.01% formic acid; gradient: 0.0 min 10% B→2.5 min 95%B→3.5 min 95% B; temperature: 50° C.; flow rate: 0.90 ml/min; UVdetection: 210 nm/optimum integration path 210-300 nm.

Method 3 (LC-MS):

MS instrument: Waters Micromass QM; HPLC instrument: Agilent 1100series; column: Agilent ZORBAX Extend-C18 3.5 μm, 50 mm×3.0 mm; mobilephase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1l of acetonitrile; gradient: 0.0 min 98% A→0.2 min 98% A→3.0 min 5%A→4.5 min 5% A; temperature: 40° C.; flow rate: 1.75 ml/min; UVdetection: 210 nm.

Method 4 (LC-MS):

MS instrument: Waters Micromass Quattro Micro; HPLC instrument: WatersUPLC Acquity; column: Waters BEH C18 1.7 μm, 50 mm×2.1 mm; mobile phaseA: 1 l of water+0.01 mol of ammonium formate, mobile phase B: 1 l ofacetonitrile; gradient: 0.0 min 95% A→0.1 min 95% A→2.0 min 15% A→2.5min 15% A→2.51 min 10% A→3.0 min 10% A; temperature: 40° C.; flow rate:0.5 ml/min; UV detection: 210 nm.

Method 5 (LC-MS):

Instrument: Agilent MS Quad 6150 with HPLC Agilent 1290; column: WatersAcquity UPLC HSS T3 1.8 μm, 50 mm×2.1 mm; mobile phase A: 1 l ofwater+0.25 ml of 99% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90%A→0.3 min 90% A→1.7 min 5% A→3.0 min 5% A; flow rate 1.20 ml/min;temperature: 50° C.; UV detection: 205-305 nm.

Method 6 (LC-MS):

MS instrument: Waters Single Quad MS-System; HPLC instrument: WatersUPLC Acquity; column: Waters BEH C18 1.7 μm, 50 mm×2.1 mm; mobile phaseA: 1 l of water+1.0 ml of 25% strength ammonia; mobile phase B: 1 l ofacetonitrile; gradient: 0.0 min 92% A→0.1 min 92% A→1.8 min 5% A→3.5 min5% A; temperature: 50° C.; flow rate: 0.45 ml/min; UV detection: 210 nm(208-400 nm).

Method 7 (LC-MS):

MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: ZorbaxSB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025%formic acid, mobile phase B: acetonitrile+0.025% formic acid; gradient:0.0 min 98% A→0.9 min 25% A→1.0 min 5% A→1.4 min 5% A→1.41 min 98% A→1.5min 98% A; temperature: 40° C.; flow rate: 0.60 ml/min; UV detection:DAD, 210 nm.

Method 8 (preparative HPLC):

Instrument: Abimed Gilson 305; column: Reprosil C18 10 μm, 250 mm×30 mm;mobile phase A: water, eluent B: acetonitrile; gradient: 0-3 min 10% B,3-27 min 10% B→95% B, 27-34.5 min 95% B, 34.5-35.5 min 95% B→10% B,35.5-36.5 min 10% B; flow rate: 50 ml/min; room temperature; UVdetection: 210 nm.

Method 9 (preparative HPLC):

Instrument: Knauer P 2.1 L-Azura; column: Chromatorex C18 10 μm, 125mm×40 mm; mobile phase A: water, eluent B: acetonitrile; gradient: 0-3min 20% B, 3-21 min 20% B→95% B, 21-24 min 95% B, 24-25 min 95% B→20% B,25-27.5 min 20% B; flow rate: 100 ml/min; room temperature; UVdetection: 210 nm.

Method 10 (preparative HPLC):

Instrument: Knauer P 2.1 L-Azura; column: Reprosil C18 10 μm, 250 mm×30mm; mobile phase A: water, eluent B: acetonitrile; gradient: 0-5 min 10%B, 5-19 min 10% B→50% B, 19-20 min 50% B→95% B, 20-25 min 95% B, 25-26min 95% B→10% B, 26-28.5 min 10% B; flow rate: 100 ml/min; roomtemperature; UV detection: 210 nm.

Method 11 (LC-MS):

Instrument: Shimadzu LCMS-2020; column Kinetex 2.6 μm XB-C18 H16-198547,50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid,mobile phase B: acetonitrile; gradient: 0.0 min 5% B→1.2 min 100% B→1.8min 100% B→1.9 min 5% B→2.0 min 5% B; flow rate: 1.50 ml/min; UVdetection: 190-400 nm; temperature: 40° C.

Method 12 (LC-MS):

Instrument: Shimadzu MS 2020 with LC Shimadzu 20ADxr; column: Kinetex2.6 μm XB-C18, 50 mm×3.0 mm; mobile phase A: water with 0.05%trifluoroacetic acid, mobile phase B: acetonitrile; gradient: 0.0 min 5%B→2.0 min 80% B→1.8 min 80% B→2.9 min 5% B→3.0 min 5% B; flow rate: 1.50ml/min; UV detection: 190-400 nm; temperature: 40° C.

Method 13 (LC-MS):

Instrument: Shimadzu shim-pack XR-ODS; column: Kinetex 2.6 μm XB-C1840332846, 50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroaceticacid, mobile phase B: acetonitrile; gradient: 0.0 min 5% B→1.2 min 100%B→2.2 min 100% B→2.25 min 5% B→2.6 min 5% B; flow rate: 1.50 ml/min; UVdetection: 190-400 nm; temperature: 40° C.

Method 14 (LC-MS):

Instrument: Shimadzu LCMS-2020; column Kinetex 2.6 μm XB-C18 H15-179292,50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid,mobile phase B: acetonitrile; gradient: 0.0 min 5% B→1.2 min 100% B→1.8min 100% B→1.9 min 5% B→2.0 min 5% B; flow rate: 1.50 ml/min; UVdetection: 190-400 nm; temperature: 40° C.

Method 15 (LC-MS):

Instrument: Shimadzu LCMS-2020; column Kinetex 2.6 m XB-C18 H16-198547,50 mm×3.0 mm; mobile phase A: water with 0.05% trifluoroacetic acid,mobile phase B: acetonitrile; gradient: 0.0 min 5% B→4.0 min 80% B→4.8min 80% B→4.9 min 5% B→5.0 min 5% B; flow rate: 1.50 ml/min; UVdetection: 190-400 nm; temperature: 40° C.

Further Details:

The percentages in the example and test descriptions which follow are,unless indicated otherwise, percentages by weight; parts are parts byweight. Solvent ratios, dilution ratios and concentration data forliquid/liquid solutions are based in each case on volume.

Purity figures are generally based on corresponding peak integrations inthe LC/MS chromatogram, but may additionally also have been determinedwith the aid of the ¹H NMR spectrum. If no purity is stated, the purityis generally >95% according to automated peak integration in the LC/MSchromatogram, or the purity has not been determined explicitly.

Stated yields in % of theory are generally corrected for purity if apurity of <100% is indicated. In solvent-containing or contaminatedbatches, the formal yield may be “>100%”; in these cases the yield isnot corrected for solvent or purity.

In cases where the reaction products were obtained by trituration,stirring or recrystallization, it was frequently possible to isolatefurther amounts of product from the respective mother liquor bychromatography. However, a description of this chromatography isdispensed with hereinbelow unless a large part of the total yield couldonly be isolated in this step.

Melting points and melting point ranges, if stated, are uncorrected.

The descriptions of the coupling patterns of ¹H NMR signals that followhave in some cases been taken directly from the suggestions of the ACDSpecManager (ACD/Labs Release 12.00, Product version 12.5) and have notnecessarily been strictly scrutinized. In some cases, the suggestions ofthe SpecManager were adjusted manually. Manually adjusted or assigneddescriptions are generally based on the optical appearance of thesignals in question and do not necessarily correspond to a strict,physically correct interpretation. In general, the stated chemical shiftrefers to the center of the signal in question. In the case of broadmultiplets, an interval is given. Signals obscured by solvent or waterwere either tentatively assigned or have not been listed.

The ¹H NMR data of synthesis intermediates and working examples can alsobe stated in the form of ¹H NMR peak lists. Here, for each signal peak,first the δ value in ppm and then the signal intensity in round bracketsare listed. The δ value/signal intensity number pairs of differentsignal peaks are listed separated by commas; accordingly, the peak listfor a compound has the form: δ₁ (intensity₁), δ₂ (intensity), . . . ,δ_(i) (intensity_(i)), . . . , δ_(n)(intensity_(n)).

The intensity of sharp signals correlates with the height of the signals(in cm) in a printed example of an NMR spectrum and shows the trueratios of the signal intensities in comparison with other signals. Inthe case of broad signals, several peaks or the middle of the signal andtheir relative intensity may be given in comparison to the most intensesignal in the spectrum. The lists of the ¹H NMR peaks are similar to theconventional ¹H NMR printouts and thus usually contain all peaks listedin a conventional NMR interpretation. In addition, like classic ¹H NMRprintouts, they may comprise solvent signals, signals of stereoisomersof the target compound in question, peaks of impurities, ¹³C satellitepeaks and/or rotation side bands. Peaks of stereoisomers of the targetcompound and/or peaks of impurities usually have a lower intensity onaverage than the peaks of the target compound (for example with a purityof >90%). Such stereoisomers and/or impurities may be typical of theparticular preparation process. Their peaks can thus help in identifyingreproduction of the preparation process with reference to “by-productfingerprints”. An expert calculating the peaks of a target compound byknown methods (MestreC, ACD simulation, or using empirically determinedexpected values) can, if required, isolate the peaks of the targetcompound, optionally using additional intensity filters. This isolationwould be similar to the peak picking in question in conventional ¹H NMRinterpretation.

A detailed description of the presentation of NMR data in the form ofpeak lists can be found in the publication “Citation of NMR PeaklistData within Patent Applications” (seehttp://www.researchdisclosure.com/searching-disclosures, ResearchDisclosure Database Number 605005, 2014, 1 Aug. 2014). In the peakpicking routine described in the stated Research Disclosure, theparameter “MinimumHeight” can be set between 1% and 4%. However,depending on the type of chemical structure and/or on the concentrationof the compound to be analysed, it may also be advisable to set theparameter “MinimumHeight” to values of <1%.

All reactants or reagents whose preparation is not described explicitlyhereinafter were purchased commercially from generally accessiblesources. For all other reactants or reagents whose preparation islikewise not described hereinafter and which were not commerciallyobtainable or were obtained from sources which are not generallyaccessible, a reference is given to the published literature in whichtheir preparation is described.

Starting Compounds and Intermediates:

Example 1A 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine

Sodium bicarbonate (10.8 g, 128 mmol) was added to a solution of2-bromo-1-(4-chlorophenyl)ethanone (20.0 g, 85.7 mmol) andpyrimidin-2-amine (8.96 g, 94.2 mmol) in 200 ml of ethanol, and themixture was stirred at 80° C. for 5 hours. The batch was then cooled to0° C. (ice bath). The resulting precipitate was filtered off and washedtwice with an ethanol/water mixture (1:1). The solid was then driedunder reduced pressure at 40° C. overnight. This gave 15.9 g (69.23mmol, 80.8% of theory) of the target product.

LC-MS (method 2): R_(t)=1.25 min; m/z=230 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.07 (dd, 1H), 7.53 (d, 2H), 8.03 (d,2H), 8.41 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H).

Example 2A 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine

Sodium bicarbonate (0.52 g, 6.22 mmol) was added to a solution or2-bromo-1-(4-isopropylphenyl)ethanone (1.0 g, 4.15 mmol) andpyrimidin-2-amine (0.43 g, 4.6 mmol) in 50 ml of ethanol, and themixture was stirred at 80° C. for 5 hours. The mixture was thenconcentrated to dryness. The residue was stirred with diethyl ether andthe solid that remained was filtered off and dried at 40° C. underreduced pressure overnight. This gave 1.15 g of the crude targetproduct, which was used in the subsequent reactions without furtherpurification.

LC-MS (method 2): R_(t)=1.48 min; m/z=238 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 1.24 (d, 6H), 2.87-3.00 (m, 1H), 7.04(dd, 1H), 7.34 (d, 2H), 7.92 (d, 2H), 8.21 (d, 1H), 8.33 (s, 1H), 8.51(dd, 1H).

Example 3A 2-(4-Chlorophenyl)imidazo[1,2-a]pyridine

To a solution of 20 g (85.65 mmol) of 2-bromo-1-(4-chlorophenyl)ethanoneand 8.87 g (94.22 mmol) of pyridin-2-amine in 200 ml of ethanol wereadded 10.95 g (130 mmol) of sodium hydrogencarbonate, and the mixturewas stirred at 80° C. for 5 hours. The mixture was then cooled, first toroom temperature and then to 0° C. (ice bath). The resulting precipitatewas filtered off and washed repeatedly with an ethanol/water mixture(2:1). The solid was then dried under reduced pressure at 40° C.overnight. This gave 19.8 g of the target product, which was used in thesubsequent reactions without further purification.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 6.87-6.94 (m, 1H), 7.23-7.29 (m, 1H),7.50 (d, 2H), 7.58 (d, 1H), 7.99 (d, 2H), 8.43 (s, 1H), 8.53 (d, 1H).

LC-MS (method 1): R_(t)=0.58 min; m/z=229/231 (M+H)⁺.

Example 4A 2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridine

5 g (32.14 mmol) of 1-(5-chloropyridin-2-yl)ethanone, 6.96 g (73.92mmol) of pyridin-2-amine and 9.79 g (38.56 mmol) of iodine were stirredat 120° C. for 2 h. After cooling to room temperature, 15 ml of waterand 1.93 g (48 mmol) of sodium hydroxide were added and then thereaction mixture was stirred at 100° C. for another 1 h. Thereafter, themixture was cooled to room temperature and the precipitate obtained wasfiltered off and washed repeatedly with water. The solid was dissolvedin cyclohexane/ethyl acetate (1:1), silica gel was added, the mixturewas concentrated to dryness again and the residue was purified by columnchromatography on silica gel (mobile phase: cyclohexane/ethyl acetate1:1). 4.32 g (18.81 mmol, 59% of theory) of the target compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 6.95 (t, 1H), 7.30 (t, 1H), 7.61 (d,1H), 8.00 (dd, 1H), 8.12 (d, 1H), 8.50 (s, 1H), 8.59 (d, 1H), 8.65 (d,1H).

LC-MS (method 1): R_(t)=0.50 min; m/z=230/232 (M+H)⁺.

Analogously to Examples 1A-4A, the following compounds were preparedfrom the starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 5A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 7.07 (dd, 1H), 7.67 (d, 2H), 7.97(d, 2H), 8.42 (s, 1H), 8.54 (dd, 1H), 8.97 (dd, 1H). LC-MS (method 2):R_(t) = 1.34 min; m/z = 274/276 (M + H)⁺. 6A

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 6.88-6.94 (m, 1H), 7.23- 7.29 (m, 1H),7.58 (d, 1H), 7.63 (d, 2H), 7.92 (d, 2H), 8.44 (s, 1H), 8.53 (d, 1H).LC-MS (method 1): R_(t) = 0.63 min; m/z = 273/275 (M + H)⁺. 7A

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 1.23 (d, 6H), 2.85-2.96 (m, 1H), 6.88(t, 1H), 7.19-7.26 (m, 1H), 7.31 (d, 2H), 7.56 (d, 1H), 7.88 (d, 2H),8.34 (s, 1H), 8.51 (d, 1H). LC-MS (method 1): R_(t) = 0.68 min; m/z =237 (M + H)⁺.

Example 8A 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

300 ml of DMF were initially charged and cooled to 0° C. Phosphorusoxychloride (16 ml, 173 mmol) was then slowly added dropwise. Thesolution was then slowly warmed to room temperature and stirred at thistemperature for another hour. 2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidine(15.9 g, 69.2 mmol) was then added a little at a time. After theaddition had ended, the reaction mixture was heated to 80° C. andstirred at this temperature for 1 hour. The batch was then cooled to 0°C. (ice bath). The resulting solid was filtered off with suction, washedrepeatedly with water and dried in a high-vacuum drying cabinet at 40°C. overnight. 13.75 g (53.36 mmol, 77% of theory) of the target productwere obtained.

LC-MS (method 2): R_(t)=1.44 min; m/z=258 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.46 (dd, 1H), 7.65 (d, 2H), 8.01 (d,2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H).

Example 9A 2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde

50 ml of DMF were initially charged and cooled to 0° C. Phosphorusoxychloride (2.86 ml, 30.66 mmol) was then slowly added dropwise. Thesolution was then slowly warmed to room temperature and stirred at thistemperature for another hour.2-(4-Isopropylphenyl)imidazo[1,2-a]pyrimidine (2.91 g, 12.26 mmol) wasthen added a little at a time. After the addition had ended, thereaction mixture was heated to 80° C. and stirred at this temperaturefor 1 hour. The batch was then cooled to 0° C. (ice bath). The solidobtained was filtered off with suction and dried under reduced pressure.The resulting crude product was subsequently purified twice by columnchromatography (Biotage Isolera, Biotage SNAP-KP-NH column, mobile phasecyclohexane/ethyl acetate gradient). 3 g (11.3 mmol, 92% of theory) ofthe target compound were obtained.

LC-MS (method 2): R_(t)=1.75 min; m/z=266 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.27 (d, 6H), 3.00 (dt, 1H),7.39-7.52 (m, 3H), 7.90 (d, 2H), 8.89 (dd, 1H), 9.83 (dd, 1H), 10.08 (s,1H).

Example 10A 2-(4-Chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde

300 ml of DMF were cooled to 0° C. 44 ml (470.08 mmol) of phosphorusoxychloride were then slowly added dropwise. The reaction solution wasthen slowly warmed to room temperature and stirred at this temperaturefor another hour. 43 g (188.03 mmol) of2-(4-chlorophenyl)imidazo[1,2-a]pyridine were then added in portions.During the addition, the reaction solution warmed to 35° C. After theaddition had ended, the reaction mixture was heated to 80° C. andstirred at this temperature for 2 hours. After cooling to roomtemperature, the solution was slowly added to 3 litres of ice-water. Theresulting solid was filtered off with suction, washed repeatedly withwater and dried in a high-vacuum drying cabinet at 40° C. overnight.39.6 g (154.27 mmol, 82% of theory) of the target product were obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.37 (t, 1H), 7.63 (d, 2H), 7.78 (t,1H), 7.90-7.99 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H).

LC-MS (method 1): R_(t)=0.97 min; m/z=257/259 (M+H)⁺.

Example 11A2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde

80 ml of DMF were cooled to 0° C. 4.4 ml (47.02 mmol) of phosphorusoxychloride were then slowly added dropwise. The reaction solution wasthen slowly warmed to room temperature and stirred at this temperaturefor another hour. 4.32 g (18.81 mmol) of2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine were then added inportions. When the addition had ended, the reaction mixture was heatedto 80° C. and stirred at this temperature for 1 h. After cooling to roomtemperature, the solution was gradually added to ice-water. Ethylacetate was added and, after thorough shaking, the organic phase wasremoved. The latter was washed with saturated sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to dryness. Theresidue obtained was purified by column chromatography on silica gel(mobile phase: cyclohexane/ethyl acetate 2:1). cyclohexane/ethyl acetate2:1). 4.46 g (17.31 mmol, 92% of theory) of the target compound wereobtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.36 (td, 1H), 7.76 (ddd, 1H), 7.94(d, 1H), 8.15 (dd, 1H), 8.35 (d, 1H), 8.81 (d, 1H), 9.60 (d, 1H), 10.87(s, 1H).

LC-MS (method 1): R_(t)=0.92 min; m/z=258/260 (M+H)⁺.

Analogously to Examples 8A-11A, the following compounds were preparedfrom the starting material specified in each case:

Example Name/Structure/Starting material Analytical data 12A

¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 7.46 (dd, 1H), 7.79 (d, 2H), 7.94(d, 2H), 8.91 (dd, 1H), 9.83 (dd, 1H), 10.07 (s, 1H). LC-MS (method 1):R_(t) = 0.78 min; m/z = 302/304 (M + H)⁺. 13A

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.35 (t, 1H), 7.72-7.80 (m, 3H),7.85-7.95 (m, 3H), 9.58 (d, 1H), 10.02 (s, 1H). LC-MS (method 2): R_(t)= 1.76 min; m/z = 301/303 (M + H)⁺. 14A

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 1.27 (d, 6H), 2.93-3.05 (m, 1H), 7.33(t, 1H), 7.44 (d, 2H), 7.74 (t, 1H), 7.85 (d, 2H), 7.91 (d, 1H), 9.58(d, 1H), 10.03 (s, 1H). LC-MS (method 1): R_(t) = 1.03 min; m/z = 265(M + H)⁺.

Example 15A 2,2′-Oxydiacetaldehyde

With stirring, a solution of 2,5-dihydrofuran (50 g, 713.37 mmol) in 1.2litres of dichloromethane was cooled to −78° C. Excess ozone was thenintroduced into the reaction solution until the blue colour remained.Thereafter, nitrogen was introduced for 30 min. When the introduction ofnitrogen had ended, 185.8 g (218.6 ml, 2.99 mol) of dimethyl sulfidewere added to the reaction solution. The reaction mixture was thenslowly warmed to room temperature and stirred for 15 hours (reactionmonitored by TLC: mobile phase petroleum ether/ethyl acetate 2:1;starting material 2,5-dihydrofuran R_(f)=0.3, target product R_(f)=0.1).The reaction mixture was then concentrated to dryness under reducedpressure. This gave 100 g of the title compound as a yellowish oil whichwas used in the subsequent reaction without further purification.

Example 16A 9-Benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one

71.5 g (490 mmol) of 3-oxopentanedicarboxylic acid and 40.1 g (490 mmol)of sodium acetate were added to a solution of 2,2′-oxydiacetaldehyde(100 g, about 980 mmol) in 600 ml of water. A little at a time, 52.5 g(490 mmol) of benzylamine, dissolved in 200 ml of 3 N hydrochloric acid,were then added and the mixture was stirred at 25° C. for 16 h. The pHof the reaction mixture was then adjusted to pH 10 using 1 N aqueoussodium hydroxide solution and the solution was extracted three timeswith 1 litre of ethyl acetate. The combined organic phases wereconcentrated to dryness under reduced pressure. The residue obtained wasseparated into its components on silica gel (mobile phase:dichloromethane). This gave 36 g (155.65 mmol, 16% of theory) of thetitle compound.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=7.44-7.31 (m, 5H), 3.92 (s, 2H), 3.84(d, 2H), 3.72 (d, 2H), 3.18-3.16 (m, 2H), 2.78-2.73 (m, 2H), 2.36 (s,1H), 2.33 (s, 1H).

Example 17A(E/Z)-9-Benzyl-N-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-imine

At 20°-30° C., 22.8 g (329 mmol) of hydroxylamine hydrochloride weremetered into a solution of 38 g (164 mmol) of9-benzyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one and 53.9 g (657 mmol) ofsodium acetate in 600 ml of ethanol and 200 ml of water. The reactionmixture was then heated to 70°-80° C. and stirred at this temperaturefor 3 h. After cooling, the reaction mixture was concentrated underreduced pressure, i.e. part of the solvent was removed on a rotaryevaporator. The reaction solution that remained was extracted threetimes with 500 ml of ethyl acetate. The combined organic phases weredried over sodium sulfate, filtered and concentrated to dryness. Thisgave 35 g (142.1 mmol, 87% of theory) of the title compound, which wasused in the subsequent reaction without further purification.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=7.37-7.18 (m, 5H), 3.82-3.76 (m, 4H),3.69-3.61 (m, 2H), 3.08-3.04 (d, 1H), 2.83-2.81 (m, 2H), 2.68-2.63 (m,1H), 2.35-2.24 (m, 2H).

Example 18A 10-Benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one(racemate)

With stirring at 20°-30° C., 40.6 g (213 mmol) of4-methylbenzenesulfonyl chloride were added to a solution of 35 g (142mmol) of (E/Z)-9-benzyl-N-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-imineand 45.2 g (426 mmol) of sodium carbonate in 525 ml of acetonitrile and175 ml of water. The reaction mixture was then heated to 70°-80° C. andstirred at this temperature for 15 h. After cooling to room temperature,the reaction mixture was concentrated under reduced pressure(acetonitrile was removed under reduced pressure). The remaining aqueousphase was extracted three times with 1000 ml of ethyl acetate. Thecombined organic phases were washed with 300 ml of saturated sodiumchloride solution, dried over sodium sulfate, filtered and concentratedto dryness. This gave 25 g (101.5 mmol, 71% of theory) of the titlecompound which was reacted without further purification.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=7.37-7.18 (m, 5H), 6.00 (br. s, 1H),3.90-3.78 (m, 7H), 3.07-3.03 (m, 2H), 2.71 (br. s, 1H), 2.61 (br. s,1H), 2.41-2.37 (m, 1H).

Example 19A 10-Benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane (racemate)

Under argon and at a temperature of 20°-30° C., 4.62 g (122 mmol) oflithium aluminium hydride were added a little at a time to a solution of10 g (40.6 mmol) of 10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one(racemate) in 800 ml of dry THF. The reaction mixture was then stirredat this temperature for 12 h. In parallel, this reaction was carried outa second time. Both reaction mixtures were then cooled to 0° C., and 10ml of water, 10 ml of 10% strength aqueous sodium hydroxide solution and30 ml of water were successively added to each mixture. After filtrationof the reaction mixtures, the filtrates were combined and extractedthree times with 1 litre of ethyl acetate. The combined organic phaseswere washed with 200 ml of saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated to dryness. This gave 22g of the title compound as a brown oil which was used in the subsequentreaction without further purification.

Example 20A tert-Butyl10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (racemate)

With stirring and at a temperature of 20°-30° C., 14.1 g (64.6 mmol) ofdi-tert-butyl dicarbonate were metered into a mixture consisting of 10 g(43.0 mmol) of 10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane (racemate)and 17.9 ml (129 mmol) of triethylamine in 250 ml of dichloromethane.The reaction mixture was then stirred at this temperature for 5 h. Thereaction solution was subsequently concentrated to dryness under reducedpressure.

In parallel, this reaction was carried out a second time in exactly thesame size. The crude products obtained in this manner were combined andthen purified together by column chromatography on silica gel (mobilephase: petroleum ether/ethyl acetate 50:1→3:1). This gave in total 24 g(70.8 mmol, 82% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=7.33-7.21 (m, 5H), 3.9-3.7 (m, 2H),3.75-3.40 (m, 7H), 3.30-3.20 (m, 1H), 2.78-2.74 (m, 2H), 2.00-2.20 (m,1H), 1.75-1.60 (m, 1H), 1.50-1.40 (m, 9H).

Example 21A tert-Butyl8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (racemate)

At a temperature of 20°-30° C., 2 g (64.6 mmol) of palladium hydroxidewere added to a solution of 10 g (30.1 mmol) of tert-butyl10-benzyl-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate in 500 mlof methanol. With stirring, the reaction mixture was subsequentlyhydrogenated at this temperature under 50 psi (about 3.45 bar) ofhydrogen for 4 h. The reaction solution was subsequently filtered andthe filtrate was concentrated to dryness under reduced pressure. Onsilica gel (mobile phase: petroleum ether/ethyl acetate 50:1→1:1), theresidue obtained was separated into its components. This gave 5 g (20.6mmol, 69% of theory) of the title compound.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.92-3.85 (m, 2H), 3.71-3.59 (m, 4H),3.37-3.24 (m, 2H), 3.07-3.00 (m, 1H), 2.82-2.81 (m, 1H), 2.04-1.99 (m,2H), 1.48 (s, 9H).

Example 22A and Example 23A tert-Butyl8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (Enantiomers 1 and 2)

5.91 g (24.4 mmol) of the racemic tert-butyl8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (Example 21A) wereseparated into the enantiomers by preparative HPLC on a chiral phase[column: YMC Chiral Art Cellulose, 5 μm, 250 mm×20 mm; mobile phase:n-heptane/isopropanol 60:40 (v/v)+0.2% diethylamine; flow rate: 15ml/min; UV detection: 220 nm; temperature: 45° C.]:

Example 22A (Enantiomer 1)

Yield: 2.95 g

R_(t)=4.95 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/isopropanol 60:40 (v/v)+0.2% diethylamine; flow rate: 1ml/min; temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 4): R_(t)=1.12 min; m/z=242 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.38 (d, 9H), 1.77-1.88 (m, 2H),2.68-2.79 (m, 1H), 2.88-2.97 (m, 1H), 3.04-3.76 (m, 9H).

Example 23A (Enantiomer 2)

Yield: 2.85 g

R_(t)=6.47 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/isopropanol 60:40 (v/v)+0.2% diethylamine; flow rate: 1ml/min; temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 4): R_(t)=1.12 min; m/z=242 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.38 (d, 9H), 1.76-1.88 (m, 2H),2.66-2.81 (m, 1H), 2.87-2.98 (m, 1H), 3.04-3.79 (m, 9H).

Example 24A 2-(4-Methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one(racemate)

Under an atmosphere of nitrogen, 20 litres of DMSO, 1759 g (14.28 mol)of 4-methoxyaniline, 1083 g (37% strength aqueous solution, 13.0 mol) offormaldehyde, 2496 g (26 mol) of cyclohex-2-en-1-one and 448.5 g (3.9mol) of DL-proline were introduced into a 50 litre reactor. The reactionmixture was then heated to 50° C. and stirred at this temperature for 30h. The reaction mixture was subsequently cooled to room temperatureusing a water/ice bath and transferred into a larger vessel, and 100litres of water were added. The reaction mixture was extracted threetimes with 20 litres of ethyl acetate. The combined organic phases werewashed once with 30 litres of saturated sodium chloride solution. Afterthe organic phase had been removed, it was concentrated to dryness underreduced pressure. On silica gel (mobile phase: petroleum ether/ethylacetate 15:1), the residue obtained was separated into its components.This gave 600 g (2.60 mol, 18% of theory) of the title compound.

LC-MS (method 11): R_(t)=0.913 min; m/z=232 (M+H)⁺.

Example 25A(E/Z)-N-Hydroxy-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-imine(racemate)

Under an atmosphere of nitrogen, 600 g (2.59 mol) of2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one (racemate), 10 litresof THF, 688 g (6.43 mol) of sodium carbonate and 197 g (2.86 mol) ofhydroxylamine hydrochloride were introduced into a 20 litre four-neckedflask. The reaction mixture was then stirred at room temperatureovernight. The reaction mixture was subsequently filtered and thefiltrate was concentrated to dryness under reduced pressure. This gave700 g of the title compound which was used in the subsequent reactionwithout further purification.

LC-MS (method 11): R_(t)=0.71 min; m/z=247 (M+H)⁺.

Example 26A 6-(4-Methoxyphenyl)-2,6-diazabicyclo[3.2.2]nonan-3-one(racemate)

Under an atmosphere of nitrogen, 700 g (2.84 mol) of(E/Z)-N-hydroxy-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-imine(racemate), 3500 g of polyphosphoric acid and 1 litre of toluene wereintroduced into a 5 litre four-necked flask. The resulting reactionsolution was heated to 100° C. with stirring and stirred at thistemperature for 5 h. The reaction mixture was subsequently cooled toroom temperature using a water bath. After transfer to a larger vessel,10 litres of water were added. The resulting mixture was extracted with10 litres of ethyl acetate. After removal of the organic phase, theaqueous phase was adjusted to a pH of 10 using aqueous sodium hydroxidesolution. The solution was then extracted twice with 10 litres ofdichloromethane, and the combined organic phases were dried over sodiumsulfate, filtered and concentrated to dryness under reduced pressure.This gave 270 g (1.12 mmol, 39% of theory) of the title compound.

LC-MS (method 11): R_(t)=0.76 min; m/z=247 (M+H)⁺.

Example 27A 2,6-Diazabicyclo[3.2.2]nonan-3-one (racemate)

Under an atmosphere of nitrogen, 225 g (914 mmol) of6-(4-methoxyphenyl)-2,6-diazabicyclo[3.2.2]nonan-3-one (racemate), 2.2litres of acetonitrile and 440 ml of water were introduced into a 10litre four-necked flask. At room temperature and with stirring, 1254 g(2.29 mol) of cerium(IV) ammonium nitrate were then added to thereaction mixture a little at a time and stirring was continuedovernight. 3 litres of water were then added to the solution and the pHwas adjusted to 10 by addition of sodium carbonate. The solutionobtained in this manner was used directly, without further work-up, inthe next reaction.

LC-MS (method 11): R_(t)=0.17 min; m/z=141 (M+H)⁺.

Example 28A Benzyl 3-oxo-2,6-diazabicyclo[3.2.2]nonane-6-carboxylate(racemate)

The solution obtained in Example 27A was transferred into a 20 litreflask, and 310 g (1.82 mol) of benzyl carbonochloridate were added alittle at a time with stirring. Stirring of the resulting reactionsolution was continued at room temperature overnight. The solution wasthen filtered, and the filtrate obtained was extracted three times with3 litres of dichloromethane. The combined organic phases wereconcentrated to dryness under reduced pressure. On silica gel (mobilephase: dichloromethane/methanol 10:1), the residue obtained wasseparated into its components. This gave 120 g of the title compound(438 mmol, 48% of theory based on 225 g (914 mmol) of6-(4-methoxyphenyl)-2,6-diazabicyclo[3.2.2]nonan-3-one).

LC-MS (method 11): R_(t)=0.81 min; m/z=275 (M+H)⁺.

Example 29A Benzyl 2,6-diazabicyclo[3.2.2]nonane-6-carboxylate(racemate)

Under an atmosphere of nitrogen, 120 g (438 mmol) of benzyl3-oxo-2,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate) and 1.5litres of dry THF were introduced into a 5 litre four-necked flask. Withstirring, 547 ml (1.1 mol) of a 2 M solution of borane/dimethyl sulfidecomplex in THF were metered in a little at a time. The reaction solutionwas then heated to 65° C. and stirred at this temperature overnight.Using an ice/water bath, the reaction solution was then cooled to 0° C.,and the reaction was stopped by addition of 3 M hydrochloric acid.Hydrochloric acid was added until a pH of 2 had been reached. Theresulting solution was heated to 70° C. and stirred at this temperaturefor 1 h. The solution was subsequently cooled to room temperature, andsodium carbonate was added carefully until a pH of 10 had been reached.The solution obtained in this manner was used directly, without furtherwork-up, in the next reaction.

LC-MS (method 11): R_(t)=0.67 min; m/z=261 (M+H)⁺.

Example 30A 6-Benzyl 2-tert-butyl2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (racemate)

Under an atmosphere of nitrogen, the solution obtained in Example 29Awas transferred into a 5 litre four-necked flask, and 191 g (875 mmol)of di-tert-butyl dicarbonate were added. The resulting solution wasstirred at room temperature for 3 h. 3 litres of water were then addedslowly. The solution was extracted three times with ethyl acetate, andthe organic phases were combined and concentrated to dryness underreduced pressure. On silica gel (mobile phase: petroleum ether/ethylacetate 10:1), the residue obtained was separated into its components.This gave 100 g of the title compound (278 mmol, 63% of theory based on120 g (438 mmol) of benzyl3-oxo-2,6-diazabicyclo[3.2.2]nonane-6-carboxylate).

LC-MS (method 11): R_(t)=1.23 min; m/z=361 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.37 (s, 5H), 5.16 (s, 2H), 4.53-4.28(m, 2H), 3.93-3.75 (m, 2H), 3.35-3.19 (m, 2H), 2.06-1.70 (m, 6H), 1.48(s, 9H).

Example 31A and Example 32A 6-Benzyl 2-tert-butyl2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (Enantiomers 1 and 2)

100 g (277 mmol) of racemic 6-benzyl 2-tert-butyl2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (Example 30A) wereseparated into the enantiomers by preparative SFC-HPLC on a chiral phase[column: ColumnTEK EnantioPak-Al, 5 μm, 250 mm×50 mm; mobile phase:carbon dioxide/ethanol 50:50 (v/v); flow rate: 150 ml/min; pressure: 100bar; UV detection: 220 nm; temperature: 35° C.]:

Example 31A (Enantiomer 1)

Yield: 30 g

R_(t)=1.88 min; >98% ee

[column: Daicel Chiralpak ID-H, 5 μm, 150 mm×4.6 mm; mobile phase:carbon dioxide/methanol 10:90 (v/v)+0.1% diethylamine; flow rate: 4ml/min; pressure: 100 bar; UV detection: 210 nm; temperature: 35.8° C.].

Example 32A (Enantiomer 2)

Yield: 30 g

R_(t)=2.29 min; >99% ee

[column: Daicel Chiralpak ID-H, 5 μm, 150 mm×4.6 mm; mobile phase:carbon dioxide/methanol 10:90 (v/v)+0.1% diethylamine; flow rate: 4ml/min; pressure: 100 bar; UV detection: 210 nm; temperature: 35.8° C.].

Example 33A tert-Butyl 2,6-diazabicyclo[3.2.2]nonane-2-carboxylate(Enantiomer 1)

At room temperature, 25 g (69.4 mmol) of 6-benzyl 2-tert-butyl2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (enantiomer 1), 250 mlof methanol and 4 g (3.7 mmol) of palladium on carbon (10%) wereintroduced into a 1 litre flask. With stirring, the reaction mixture wassubsequently hydrogenated at room temperature under 1 bar of hydrogenovernight. The reaction solution was subsequently filtered and thefiltrate was concentrated under reduced pressure. The residue was thenwashed once with 50 ml of hexane. The precipitate that remained wasfiltered off and dried in a vacuum drying oven at 40° C. This gave 10.1g (44.4 mmol, 64% of theory) of the title compound.

LC-MS (method 12): R_(t)=0.85 min; m/z=227 (M+H)⁺.

¹H-NMR (300 MHz, D₂O): δ [ppm]=4.21-4.15 (m, 1H), 3.90-3.34 (m, 2H),3.26-2.82 (m, 3H), 1.88-1.65 (m, 6H), 1.35 (s, 9H). [α]_(D)^(27.2)=−17.41° (c=0.494 g/100 ml in methanol).

Example 34A tert-Butyl 2,6-diazabicyclo[3.2.2]nonane-2-carboxylate(Enantiomer 2)

At room temperature, 25 g (69.4 mmol) of 6-benzyl 2-tert-butyl2,6-diazabicyclo[3.2.2]nonane-2,6-dicarboxylate (enantiomer 2), 250 mlof methanol and 4 g (3.7 mmol) of palladium on carbon (10%) wereintroduced into a 1 litre flask. With stirring, the reaction mixture wassubsequently hydrogenated at room temperature under 1 bar of hydrogenovernight. The reaction solution was subsequently filtered and thefiltrate was concentrated under reduced pressure. The residue was thenwashed once with 50 ml of hexane. The precipitate that remained wasfiltered off and dried in a vacuum drying oven at 40° C. This gave 10.9g (47.8 mmol, 69% of theory) of the title compound.

LC-MS (method 12): R_(t)=0.84 min; m/z=227 (M+H)⁺.

¹H-NMR (300 MHz, D₂O): δ [ppm]=4.31-4.21 (m, 1H), 4.10-3.41 (m, 2H),3.22-3.04 (m, 3H), 1.97-1.63 (m, 6H), 1.36 (s, 9H).

[α]_(D) ^(27.2)=+16.590 (c=0.476 g/100 ml in methanol).

Example 35A 3-Benzyl-(E/Z)-N-hydroxy-3-azabicyclo[3.2.1]octan-8-imine

200 g (930 mmol) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one, 64.6 g (930mmol) of hydroxylamine hydrochloride, 120 g (929 mmol) ofdiisopropylethylamine and 1 litre of ethanol were introduced into a 1litre flask. The resulting solution was heated to 35° C. and stirred atthis temperature for 2 h. After cooling to room temperature, thesolution was concentrated under reduced pressure and transferred into alarger vessel, and 2 litres of water were added. The solution was thenextracted three times with 800 ml of dichloromethane. The organic phaseswere combined and the solution was then concentrated to dryness underreduced pressure. On silica gel (mobile phase: petroleum ether/ethylacetate 4:1 to 15:1), the residue obtained was separated into itscomponents. This gave 179 g (780 mmol, 84% of theory) of the titlecompound.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=9.53 (s, 1H), 7.39-7.26 (m, 3H), 7.20(d, 2H), 6.96 (d, 2H), 5.55 (s, 2H).

LC-MS (method 11): R_(t)=0.54 min; m/z=231 (M+H)⁺.

Example 36A 3-Benzyl-3,6-diazabicyclo[3.2.2]nonan-7-one (racemate)

800 g of polyphosphoric acid were introduced into a 3 litre four-neckedflask and heated to 50° C. 178 g (773 mmol) of8-benzyl-(E/Z)-N-hydroxy-8-azabicyclo[3.2.1]octan-3-imine, dissolved in300 ml of toluene, were then added a little at a time with stirring.After the addition had ended, the reaction mixture was heated to110°-120° C. and stirred at this temperature for 2 h. The solution wasthen cooled to 80° C., and the reaction was stopped by addition of 500ml of water. The resulting solution was slowly taken up in 5 litres ofwater. While stirring, the pH was adjusted to 10-11 by addition of 2 Maqueous sodium hydroxide solution. The solution was then extracted fourtimes with 2 litres of dichloromethane. The combined organic phases weredried over sodium sulfate and the solution was, after filtration,concentrated to dryness under reduced pressure. The solid obtained waswashed three times with 400 ml of diethyl ether and, after anotherfiltration, dried. This gave 88 g (379 mmol, 49% of theory) of the titlecompound.

LC-MS (method 11): R_(t)=0.49 min; m/z=231 (M+H)⁺.

Example 37A 3-Benzyl-3,6-diazabicyclo[3.2.2]nonane (racemate)

Under an atmosphere of nitrogen, a solution of 331 g (1.64 mol) ofsodium bis(2-methoxyethoxy)aluminiumhydride (Red-Al®) in 150 ml of dryTHF was introduced into a 3 litre four-necked flask. 88 g (382.1 mmol)of 3-benzyl-3,6-diazabicyclo[3.2.2]nonan-7-one (racemate), dissolved in1 litre of dry THF, were then added dropwise over 30 min with stirring.During the addition, the temperature of the reaction solution was keptbelow 5° C. After the addition had ended, the reaction solution washeated to 50° C. and stirred at this temperature for 3 h. The reactionmixture was cooled to 30° C., and 1 litre of ice-water was then addedslowly to stop the reaction. The pH was then adjusted to 10 by additionof 1 M aqueous sodium hydroxide solution. The resulting solution wasextracted with 500 ml of toluene. The organic phase was separated offand then washed successively with in each case 500 ml of 1 M aqueoussodium hydroxide solution, water and saturated sodium chloride solution.The organic phase was then dried over sodium sulfate, filtered andconcentrated to dryness under reduced pressure. This gave 89.7 g (crudeproduct) of the title compound as a yellowish oil which was used in thesubsequent reaction without further purification.

LC-MS (method 11): R_(t)=0.46 min; m/z=217 (M+H)⁺.

Example 38A Benzyl 3-benzyl-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate(racemate)

Under an atmosphere of nitrogen, 89.7 g (about 379 mmol, crude material)of 3-benzyl-3,6-diazabicyclo[3.2.2]nonane (racemate) in 1 litre ofdichloromethane and 57.6 g (569 mmol) of triethylamine were introducedinto a 3 litre four-necked flask. Over a period of 20 min, 64.6 g (379mmol) of benzyl carbonochloridate were then added dropwise withstirring. During the addition, the temperature of the reaction solutionwas kept below 10° C. The resulting reaction solution was stirred at 10°C. for 1 h. The solution was then diluted with 1 litre of water andextracted twice with 300 ml of dichloromethane. The combined organicphases were dried over sodium sulfate, filtered and concentrated todryness under reduced pressure. This gave 147 g (crude product) of thetitle compound as a yellowish oil which was used in the subsequentreaction without further purification.

LC-MS (method 13): R_(t)=1.05 min; m/z=351 (M+H)⁺.

Example 39A Benzyl 3,6-diazabicyclo[3.2.2]nonane-6-carboxylate(racemate)

Under an atmosphere of nitrogen, 147 g (about 378 mmol, crude material)of benzyl 3-benzyl-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate(racemate) were introduced into 1 litre of 1,2-dichloroethane in a 2litre flask. 269.8 g (1.89 mol) of 1-chloroethyl carbonochloridate werethen slowly added dropwise with stirring. The resulting reactionsolution was heated to 85° C. and stirred at this temperature for 5 h.The reaction solution was then concentrated under reduced pressure, and500 ml of methanol were added a little at a time. The solution wassubsequently stirred at 85° C. for a further hour. Then the reactionmixture was cooled to room temperature and concentrated to dryness underreduced pressure. This gave 150 g (crude product) of the title compoundas a brownish oil which was used in the subsequent reaction withoutfurther purification.

LC-MS (method 13): R_(t)=0.95 min; m/z=261 (M+H)⁺.

Example 40A 6-Benzyl 3-tert-butyl3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (racemate)

150 g (about 379 mmol, crude material) of benzyl3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (racemate) in 800 ml ofdichloromethane, 96 g (949 mmol) of triethylamine and 2.3 g (18.8 mmol)of 4-dimethylaminopyridine were introduced into a 3 litre four-neckedflask. Over a period of 40 min, 82.8 g (379.4 mmol) of di-tert-butyldicarbonate in 400 ml of dichloromethane were then added dropwise.During the addition, the temperature of the reaction solution was keptbelow 10° C. After the addition had ended, the reaction solution wasstirred at 10° C. for another 2 h. Thereafter, 1 litre of water wasadded to the solution. The organic phase was removed and then washedsuccessively with 1 litre of water and 500 ml of saturated sodiumchloride solution, dried over sodium sulfate, filtered and concentratedto dryness under reduced pressure. On silica gel (mobile phase:petroleum ether/THF 15:1), the residue obtained was separated into itscomponents. This gave 95 g (263 mmol, 69% of theory) of the titlecompound.

LC-MS (method 11): R_(t)=1.24 min; m/z=361 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.40-7.29 (m, 5H), 5.17 (s, 2H),4.53-4.03 (m, 3H), 3.66-3.51 (m, 1H), 3.39-3.29 (m, 2H), 2.33-2.26 (m,1H), 1.90-1.59 (m, 4H), 1.49 (s, 9H).

Example 41A and Example 42A 6-Benzyl 3-tert-butyl3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (Enantiomer 1 and 2)

84 g (233 mmol) of racemic 6-benzyl 3-tert-butyl3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (Example 40A) inmethanol were separated into the enantiomers by preparative SFC-HPLC ona chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×50 mm;mobile phase: carbon dioxide/ethanol 70:30 (v/v); flow rate: 150 ml/min;pressure: 100 bar; UV detection: 220 nm; temperature: 35° C.]:

Example 41A (Enantiomer 1)

Yield: 38.8 g

R_(t)=7.15 min; >95.5% ee

[column: Daicel Chiralpak AD-H, 5 μm, 100 mm×4.6 mm; mobile phase:n-hexane/isopropanol (+0.1% diethylamine) 95:5 (v/v); flow rate: 1ml/min; UV detection: 190-500 nm; temperature: 25° C.].

LC-MS (method 14): R_(t)=1.25 min; m/z=361 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.38-7.29 (m, 5H), 5.17 (s, 2H),4.53-4.03 (m, 3H), 3.66-3.51 (m, 1H), 3.39-3.29 (m, 2H), 2.33-2.26 (m,1H), 1.90-1.59 (m, 4H), 1.49 (s, 9H).

Example 42A (Enantiomer 2)

Yield: 36.9 g

R_(t)=5.15 min; >95.5% ee

[column: Daicel Chiralpak AD-H, 5 μm, 100 mm×4.6 mm; mobile phase:n-hexane/isopropanol (+0.1% diethylamine) 95:5 (v/v); flow rate: 1ml/min; UV detection: 190-500 nm; temperature: 25° C.].

LC-MS (method 14): R_(t)=1.25 min; m/z=361 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.40-7.29 (m, 5H), 5.17 (s, 2H),4.53-4.03 (m, 3H), 3.66-3.51 (m, 1H), 3.39-3.29 (m, 2H), 2.33-2.26 (m,1H), 1.90-1.59 (m, 4H), 1.49 (s, 9H).

Example 43A tert-Butyl 3,6-diazabicyclo[3.2.2]nonane-3-carboxylate(Enantiomer 1)

3 g (2.8 mmol) of palladium on carbon (10%) were introduced into asolution of 25.8 g (71.6 mmol) of 6-benzyl 3-tert-butyl3,6-diazabicyclo[3.2.1]nonane-3,6-dicarboxylate (enantiomer 1) in 250 mlof methanol. With stirring, the reaction mixture was subsequentlyhydrogenated at room temperature under 1 atm of hydrogen overnight. Thereaction solution was subsequently filtered and the filtrate wasconcentrated under reduced pressure. The residue obtained was driedunder an infrared lamp. This gave 16.0 g (70.9 mmol, 99% of theory) ofthe title compound.

LC-MS (method 15): R_(t)=1.13 min; m/z=227 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=5.06 (s, 2H), 4.06-4.49 (m, 2.4H),3.47-3.76 (m, 1H), 2.80-3.46 (m, 3.7H), 2.04-2.36 (m, 1H), 1.76-2.04 (m,1.8H), 1.56-1.72 (m, 1H), 1.48 (s, 9.2H).

[α]_(D) ^(27.2)=+9.130 (c=0.51 g/100 ml in chloroform).

Example 44A tert-Butyl 3,6-diazabicyclo[3.2.2]nonane-3-carboxylate(Enantiomer 2)

3 g (2.8 mmol) of palladium on carbon (10%) were introduced into asolution of 25 g (69.36 mmol) of 6-benzyl 3-tert-butyl3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (enantiomer 2) in 250 mlof methanol. With stirring, the reaction mixture was subsequentlyhydrogenated at room temperature under 1 atm of hydrogen overnight. Thereaction solution was subsequently filtered and the filtrate wasconcentrated under reduced pressure. The residue obtained was driedunder an infrared lamp. This gave 10.6 g (47.2 mmol, 68% of theory) ofthe title compound.

LC-MS (method 15): R_(t)=1.14 min; m/z=227 (M+H)⁺.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=4.08-4.44 (m, 2H), 3.39-3.71 (m, 2H),2.84-3.39 (m, 4.7H), 1.83-2.37 (m, 2H), 1.74 (s, 2.6H), 1.49 (s, 9H).

[α]_(D) ^(27.2)=−11.59° (c=0.52 g/100 ml in chloroform).

Example 45A2-(4-Chlorophenyl)-3-(2,6-diazabicyclo[3.2.2]non-6-ylmethyl)imidazo[1,2-a]pyrimidinebis(trifluoroacetic acid) salt (Enantiomer 2)×

tert-Butyl6-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,6-diazabicyclo[3.2.2]nonane-2-carboxylate(enantiomer 2; 1.05 g, 2.25 mmol) was initially charged in 15 ml ofdichloromethane and 7.6 ml of trifluoroacetic acid and stirred at roomtemperature overnight. The reaction mixture was then concentrated todryness. The crude product obtained in this manner was used insubsequent reactions without further purification.

LC-MS (method 2): R_(t)=0.84 min; m/z=368 (M+H)⁺.

Example 46A3-(3,9-Diazabicyclo[4.2.1]non-9-ylmethyl)-2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidinedihydrochloride (Enantiomer 1)

745 mg (1.57 mmol) of tert-butyl9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(enantiomer 1) were dissolved in 3 ml of dioxane, and 3.92 ml of a 4 Msolution of hydrogen chloride in dioxane were added with stirring. Themixture was stirred at room temperature overnight. The solids obtainedwere then filtered off with suction, washed repeatedly with diethylether and dried under high vacuum at 40° C. 720 mg of a solid materialwere obtained, which was used in subsequent reactions without furtherpurification.

LC-MS (method 1): R_(t)=0.6 min; m/z=376 (M+H)⁺.

Analogously to Examples 45A and 46A, the following compounds wereprepared from the starting material specified in each case:

Ex- Analytical ample Name/Structure/Starting material data 47A

LC-MS (method 1): R_(t) = 0.50 min; m/z = 368 (M + H)⁺. 48A

LC-MS (method 1): R_(t) = 0.38 min; m/z = 368 (M + H)⁺. 49A

LC-MS (method 2): R_(t) = 0.67 min; m/z = 367 (M + H)⁺. 50A

LC-MS (method 1): R_(t) = 0.42 min; m/z = 367 (M + H)⁺. 51A

LC-MS (method 1): R_(t) = 0.6 min; m/z = 376 (M + H)⁺. 52A

LC-MS (method 2): R_(t) = 0.97 min; m/z = 376 (M − H + HCOOH)⁻. 53A

LC-MS (method 2): R_(t) = 0.97 min; m/z = 376 (M − H + HCOOH)⁻.

Example 54A [2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methano 1

2-(4-Chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (15.0 g, 58.4mmol) was initially charged in 100 ml of ethanol and cooled to 0° C. inan ice bath. A solution of sodium borohydride (4.42 g, 117 mmol) in 50ml of ethanol was then slowly added dropwise. The mixture was stirred atroom temperature and subsequently diluted with saturated ammoniumchloride solution and with water. The precipitate formed was filteredoff with suction and washed with water. The residue was then suspendedin a little 2-methoxy-2-methylpropane and a little methanol and thenonce more evaporated to dryness. This gave 14.2 g (content 100%, 54.7mmol, 94% of theory) of the title compound.

LC-MS (method 1): R_(t)=0.49 min; m/z=259/261 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.91 (d, 2H), 5.44 (t, 1H), 7.00 (t,1H), 7.33 (t, 1H), 7.55 (d, 2H), 7.62 (d, 1H), 7.87 (d, 2H), 8.47 (d,1H).

Example 55A tert-Butyl9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Racemate)

tert-Butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (1.00 g, 4.42mmol), 3-fluoro-6-methoxypyridine-2-carboxylic acid (907 mg, 5.30 mmol)and1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium3-oxide hexafluorophosphate (2.18 g, 5.74 mmol) were initially chargedin 10 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (2.3 ml, 13.2 mmol)was then added, and the mixture was stirred at room temperatureovernight. The reaction mixture was then diluted with ethyl acetate andthe organic phase was washed with water. The organic phase was driedover magnesium sulfate, filtered and concentrated to dryness. On silicagel (mobile phase: cyclohexane/ethyl acetate gradient), the residueobtained was separated into its components. This gave 1.47 g (96% pure,3.72 mmol, 84% of theory) of the title compound.

LC-MS (method 1): R_(t)=0.98 min; m/z=380 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.35-1.46 (m, 9H), 1.47-1.61 (m,1.5H), 1.63-1.84 (m, 2H), 1.84-2.25 (m, 2H), 2.28-2.40 (m, 0.5H),2.74-3.07 (m, 1.7H), 3.26 (br. dd, 0.3H), 3.71-3.80 (m, 1H), 3.81-3.85(m, 3H), 3.86-4.06 (m, 2H), 4.57-4.76 (m, 1H), 6.97 (dt, 1H), 7.65-7.94(m, 1H).

Example 56A and Example 57A tert-Butyl9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Enantiomers 1 and 2)

1.47 g (3.72 mmol) of racemic tert-butyl9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Example 55A) were separated into the enantiomers by preparativeSFC-HPLC on a chiral phase [column: Chiralcel AD-H, 5 μm, 250 mm×30 mm;mobile phase: carbon dioxide/isopropanol 91:9 (v/v); flow rate: 125g/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 56A (Enantiomer 1)

Yield: 711 mg

R_(t)=0.93 min; chemical purity >99%; >99% ee

[column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbondioxide/isopropanol 95:5→1:1 (v/v); flow rate: 3 ml/min; pressure: 135bar; UV detection: 220 nm; temperature: 60° C.].

LC-MS (method 2): R_(t)=1.87 min; m/z=380 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.33-1.45 (m, 9H), 1.47-1.61 (m,1.5H), 1.62-1.81 (m, 2H), 1.83-2.25 (m, 2H), 2.28-2.40 (m, 0.5H),2.74-3.06 (m, 1.7H), 3.26 (br. dd, 0.3H), 3.73-3.80 (m, 1H), 3.81-3.85(m, 3H), 3.87-4.06 (m, 2H), 4.56-4.77 (m, 1H), 6.97 (dt, 1H), 7.72-7.87(m, 1H).

Example 57A (Enantiomer 2)

Yield: 695 mg

R_(t)=1.07 min; chemical purity >99%; >92% ee

[column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbondioxide/isopropanol 95:5-1:1 (v/v); flow rate: 3 ml/min; pressure: 135bar; UV detection: 220 nm; temperature: 60° C.].

LC-MS (method 2): R_(t)=1.87 min; m/z=380 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.35-1.44 (m, 9H), 1.47-1.61 (m,1.5H), 1.62-1.81 (m, 2H), 1.84-2.23 (m, 2H), 2.27-2.41 (m, 0.5H),2.72-3.08 (m, 1.7H), 3.26 (br. dd, 0.3H), 3.72-3.80 (m, 1H), 3.81-3.85(m, 3H), 3.87-4.06 (m, 2H), 4.55-4.77 (m, 1H), 6.97 (dt, 1H), 7.75-7.84(m, 1H).

Example 58A3,9-Diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 2)

tert-Butyl9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(695 mg, 1.83 mmol, enantiomer 2) was initially charged in 12 ml ofdichloromethane and 6.2 ml of trifluoroacetic acid and stirred at roomtemperature overnight. The reaction mixture was subsequently dilutedwith ethyl acetate and 1 N aqueous sodium hydroxide solution, theorganic phase was removed and the aqueous phase was extracted with ethylacetate. The combined organic phases were dried over magnesium sulfate,filtered and concentrated to dryness (LC/MS analysis was carried out atthis point). The residue obtained was dissolved in ethyl acetate andwashed with 1 N aqueous sodium hydroxide solution. The organic phase wasseparated off and the aqueous phase was once more extracted with ethylacetate. Again, the combined organic phases were dried over magnesiumsulfate, filtered and concentrated to dryness. This gave 258 mg (100%pure, 0.93 mmol, 51% of theory) of the title compound.

LC-MS (method 1): R_(t)=0.38 min; m/z=280 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25-1.78 (m, 3H), 1.80-2.28 (m, 4H),2.57-2.83 (m, 2H), 2.89-3.10 (m, 1H), 3.76-3.93 (d, 4H), 4.47-4.68 (m,1H), 6.95 (dt, 1H), 7.67-7.85 (m, 1H).

Example 59A3,9-Diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 1)

tert-Butyl9-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(711 mg, 1.87 mmol, enantiomer 1) was initially charged in 13 ml ofdichloromethane and 6.3 ml of trifluoroacetic acid and stirred at roomtemperature overnight. The reaction mixture was subsequently dilutedwith ethyl acetate and 1 N aqueous sodium hydroxide solution, theorganic phase was removed and the aqueous phase was extracted with ethylacetate. The combined organic phases were dried over magnesium sulfate,filtered and concentrated to dryness (LC/MS analysis was carried out atthis point). The residue obtained was dissolved in ethyl acetate andwashed with 1 N aqueous sodium hydroxide solution. The organic phase wasseparated off and the aqueous phase was once more extracted with ethylacetate. Again, the combined organic phases were dried over magnesiumsulfate, filtered and concentrated to dryness. This gave 309 mg (100%pure, 1.11 mmol, 59% of theory) of the title compound.

LC-MS (method 1): R_(t)=0.37 min; m/z=280 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25-1.78 (m, 3H), 1.81-2.27 (m, 4H),2.57-2.78 (m, 2H), 2.90-3.09 (m, 1H), 3.75-3.93 (d, 4H), 4.50-4.66 (m,1H), 6.95 (dt, 1H), 7.68-7.85 (m, 1H).

Example 60A tert-Butyl10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate(Enantiomer 1)

3-Fluoro-6-methoxypyridine-2-carboxylic acid (169 mg, 990 μmol) and1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium3-oxide hexafluorophosphate (408 mg, 1.07 mmol) were initially chargedin 1.0 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (430 μl, 2.5 mmol)was then added, and the mixture was stirred at room temperature for 1 h.tert-Butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (200 mg,825 μmol, enantiomer 1) in 1 ml of DMF was then added, and stirring ofthe reaction mixture was continued at room temperature overnight. Thereaction mixture was then diluted with tert-butyl methyl ether andsaturated sodium carbonate solution, the organic phase was removed andthe aqueous phase was extracted twice with ethyl acetate. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure. On silica gel (mobilephase: cyclohexane/ethyl acetate 10:1), the residue obtained wasseparated into its components. This gave 301 mg (100% pure, 0.76 mmol,92% of theory) of the title compound.

LC-MS (method 1): R_(t)=1.72 min; m/z=396 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30-1.48 (m, 9H), 1.81-2.29 (m, 2H),2.62-2.80 (m, 0.2H), 2.90-3.18 (m, 1.5H), 3.27 (br. dd, 0.4H), 3.38-3.43(m, 0.7H), 3.48-4.03 (m, 9.2H), 4.44-4.62 (m, 1H), 6.92-7.01 (m, 1H),7.81 (td, 1H).

Example 61A

tert-Butyl10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate(Enantiomer 2)

3-Fluoro-6-methoxypyridine-1-carboxylic acid (2 mg, 1.49 mmol) and1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium3-oxide hexafluorophosphate (612 mg, 1.61 mmol) were initially chargedin 1.0 ml of DMF. N-Ethyl-N-isopropylpropan-2-amine (650 μl, 3.7 mmol)was then added, and the mixture was stirred at room temperature for 1 h.tert-Butyl 8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate (300 mg,1.24 mmol, enantiomer 2) in 1 ml of DMF was then added, and stirring ofthe reaction mixture was continued at room temperature overnight. Thereaction mixture was then diluted with tert-butyl methyl ether andsaturated sodium carbonate solution, the organic phase was removed andthe aqueous phase was extracted twice with ethyl acetate. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure. On silica gel (mobilephase: cyclohexane/ethyl acetate 10:1), the residue obtained wasseparated into its components. This gave 443 mg (100% pure, 1.12 mmol,90% of theory) of the title compound.

LC-MS (method 1): R_(t)=1.72 min; m/z=396 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29-1.47 (m, 9H), 1.81-2.29 (m, 2H),2.62-2.81 (m, 0.2H), 2.89-3.21 (m, 1.5H), 3.27 (br. dd, 0.4H), 3.37-3.45(m, 0.7H), 3.47-4.03 (m, 9.2H), 4.44-4.62 (m, 1H), 6.87-7.05 (m, 1H),7.81 (td, 1H).

Example 62A(3-Fluoro-6-methoxypyridin-2-yl)(8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl)methanone(Enantiomer 1)

tert-Butyl10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate(4.53 g, 11.5 mmol, enantiomer 1) was initially charged in 40 ml ofdichloromethane and 20 ml of trifluoroacetic acid and stirred at roomtemperature for 2 h. The reaction mixture was then concentrated todryness and the residue was taken up in ethyl acetate. The organic phasewas washed with saturated sodium carbonate solution, dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure. This gave 2.36 g (content 100%, 7.98 mmol, 70% of theory) ofthe title compound.

LC-MS (method 6): R_(t)=1.00 min; m/z=296 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.57-1.80 (m, 1H), 1.82-2.11 (m, 1H),2.61-2.81 (m, 1.5H), 2.83-3.10 (m, 2.5H), 3.40-3.73 (m, 4H), 3.79-4.01(m, 4H), 4.33-4.59 (m, 1H), 6.96 (dd, 1H), 7.80 (t, 1H).

Example 63A(3-Fluoro-6-methoxypyridin-2-yl)(8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl)methanone(Enantiomer 2)

tert-Butyl10-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-8-oxa-3,10-diazabicyclo[4.3.1]decane-3-carboxylate(3.88 g, 9.80 mmol, enantiomer 2) was initially charged in 40 ml ofdichloromethane and 20 ml of trifluoroacetic acid and stirred at roomtemperature for 2 h. The reaction mixture was then concentrated todryness and the residue was taken up in ethyl acetate. The organic phasewas washed with saturated sodium carbonate solution, dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure. This gave 1.95 g (content 100%, 6.59 mmol, 67% of theory) ofthe title compound.

LC-MS (method 6): R_(t)=1.00 min; m/z=296 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.55-1.80 (m, 1H), 1.83-2.11 (m, 1H),2.63-2.81 (m, 1.5H), 2.82-3.11 (m, 2.5H), 3.39-3.73 (m, 4H), 3.79-4.01(m, 4H), 4.35-4.61 (m, 1H), 6.96 (dd, 1H), 7.80 (t, 1H).

Analogously to Examples 55A, 60A and 61A, the following compounds wereprepared from the starting materials specified in each case:

Ex- Name/Structure/Starting materials ample Analytical data 64A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.379 (5.77), 1.406 (9.63), 1.419(16.00), 1.504 (0.63), 1.528 (0.86), 1.548 (0.74), 1.571 (0.47), 1.689(0.45), 1.712 (0.83), 1.721 (0.85), 1.739 (0.90), 1.756 (0.54), 2.305(0.48), 2.336 (0.46), 2.952 (0.53), 3.699 (0.58), 3.736 (1.15), 3.770(0.64), 3.822 (0.82), 3.842 (0.79), 3.864 (0.54), 3.887 (0.48), 4.638(0.42), 4.695 (0.55), 5.755 (0.58), 7.263 (0.54), 7.270 (0.64), 7.282(1.88), 7.289 (1.90), 7.307 (1.87), 7.328 (0.70), 7.336 (0.64), 7.386(0.50), 7.403 (0.85), 7.474 (0.83), 7.488 (1.58), 7.508 (1.25). LC-MS(method 1): R_(t) = 0.99 min; m/z = 349 (M + H)⁺. 65A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.375 (6.26), 1.403 (16.00), 1.422(8.86), 1.544 (0.54), 1.558 (0.59), 1.730 (0.41), 1.744 (0.50), 1.770(0.48), 1.959 (0.41), 3.702 (0.41), 3.738 (0.54), 3.825 (0.46), 3.854(6.39), 3.867 (8.26), 4.694 (0.64), 4.708 (0.73), 4.732 (0.42), 4.761(0.40), 5.754 (1.87), 6.919 (0.65), 6.938 (0.92), 6.952 (0.72), 7.333(0.49), 7.351 (0.56), 7.800 (0.58), 7.808 (0.54), 7.819 (0.92), 7.827(0.91), 7.838 (0.57), 7.846 (0.47). LC-MS (method 1): R_(t) = 1.00 min;m/z = 362 (M + H)⁺. 66A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.358 (5.09), 1.395 (8.29), 1.411(16.00), 1.988 (0.57), 3.437 (0.45), 3.445 (0.50), 3.466 (0.70), 3.473(0.78), 3.501 (0.46), 3.569 (1.26), 3.588 (1.02), 3.597 (0.86), 3.614(0.67), 3.728 (0.58), 3.949 (0.63), 3.982 (0.47), 4.523 (0.48), 7.287(0.67), 7.296 (1.06), 7.304 (1.21), 7.318 (1.15), 7.322 (1.36), 7.341(0.54), 7.440 (0.52), 7.489 (0.40), 7.504 (0.65), 7.520 (0.52). LC-MS(method 2): R_(t) = 1.87 min; m/z = 307 (M − C₄H₉]⁺. 67A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.339 (5.79), 1.391 (11.49), 1.400(11.63), 1.404 (16.00), 1.989 (0.57), 3.141 (0.47), 3.152 (0.46), 3.412(0.46), 3.418 (0.49), 3.428 (0.54), 3.439 (0.62), 3.447 (0.50), 3.523(1.11), 3.551 (0.93), 3.567 (0.80), 3.578 (0.65), 3.587 (0.46), 3.597(0.63), 3.607 (0.67), 3.618 (0.60), 3.685 (0.77), 3.718 (0.50), 3.756(0.58), 3.787 (0.82), 3.829 (0.99), 3.847 (14.55), 3.864 (0.78), 3.959(0.89), 3.988 (0.69), 4.103 (0.46), 4.524 (0.85), 5.754 (0.42), 6.894(1.33), 6.915 (1.68), 7.112 (0.78), 7.131 (0.94), 7.153 (0.63), 7.162(0.44), 7.180 (0.44), 7.803 (0.77), 7.823 (1.33), 7.842 (0.70). LC-MS(method 2): R_(t) = 1.86 min; m/z = 378 (M + H)⁺. 68A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.227 (0.42), 1.335 (5.04), 1.387(16.00), 1.948 (0.40), 3.162 (1.47), 3.175 (1.54), 3.278 (0.42), 3.290(0.47), 3.325 (0.55), 3.498 (0.50), 3.519 (0.53), 3.527 (0.67), 3.537(0.50), 3.575 (0.53), 3.584 (0.62), 3.600 (1.23), 3.626 (1.15), 3.652(0.74), 3.692 (0.45), 3.816 (0.41), 3.841 (0.69), 3.974 (0.81), 4.002(0.83), 4.074 (0.40), 4.575 (0.75). LC-MS (method 2): R_(t) = 1.92 min;m/z = 297 [M − C₄H₉]⁺. 69A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.17), 0.008 (0.89), 1.106(0.61), 1.157 (0.55), 1.175 (1.09), 1.193 (0.56), 1.290 (10.65), 1.359(9.07), 1.369 (13.06), 1.385 (16.00), 1.398 (0.84), 1.911 (0.44), 1.944(0.46), 1.988 (2.14), 2.037 (0.52), 2.048 (0.50), 2.066 (0.42), 3.267(0.54), 3.279 (0.59), 3.510 (0.59), 3.519 (0.76), 3.528 (0.57), 3.539(0.79), 3.548 (0.99), 3.558 (0.58), 3.587 (0.47), 3.596 (0.51), 3.618(2.61), 3.630 (1.64), 3.643 (2.27), 3.657 (1.45), 3.670 (1.11), 3.778(0.45), 3.790 (0.57), 3.830 (1.06), 3.859 (0.76), 3.877 (0.57), 3.951(0.55), 3.978 (1.00), 4.004 (0.65), 4.021 (0.50), 4.039 (0.49), 4.180(0.63), 4.548 (1.30), 5.754 (0.53), 6.389 (3.00), 6.442 (1.00). LC-MS(method 1): R_(t) = 0.85 min; m/z = 354 (M + H)⁺.

Analogously to Examples 58A, 59A, 62A and 63A, the following compoundswere prepared from the starting material specified in each case:

Ex- am- ple Name/Structure/Starting material Analytical data 70A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.13-1.54 (m, 2H), 1.65-2.37 (m,5H), 2.39-2.60 (m, 2H), 2.64-3.08 (m, 2H), 3.67-3.83 (m, 1H), 4.51-4.65(m, 1H), 7.18-7.34 (m, 2H), 7.34-7.58 (m, 2H). LC-MS (method 2): R_(t) =0.58 min; m/z = 249 (M + H)⁺. 71A

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.28-1.60 (m, 1H), 1.66-2.24 (m,5H), 2.40-2.48 (m, 0.8H), 2.59-2.70 (m, 1.2H), 2.72- 2.86 (m, 1H),2.88-3.05 (m, 1H), 3.11-3.22 (m, 0.7H), 3.85 (d, 3H), 4.08 (q, 0.3H),4.35-4.58 (m, 1H), 4.56- 4.70 (m, 2H), 6.90 (dd, 1H), 7.25 (dd, 1H),7.80 (td, 1H). LC-MS (method 2): R_(t) = 0.61 min; m/z = 262 (M + H)⁺.72A

LC-MS (method 6): R_(t) = 0.94 min; m/z = 265 (M + H)⁺. 73A

LC-MS (method 6): R_(t) = 0.91 min; m/z = 278 (M + H)⁺. 74A

LC-MS (method 6): R_(t) = 0.94 min; m/z = 253 (M + H)⁺. 75A

LC-MS (method 6): R_(t) = 0.79 min; m/z = 254 (M + H)⁺.

Example 76A and Example 77A

tert-Butyl9-[(6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Enantiomers 1 and 2)

553 mg (1.53 mmol) of racemic tert-butyl9-[(6-methoxypyridin-2-yl)carbonyl]-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Example 65A) were separated into the enantiomers by preparativeSFC-HPLC on a chiral phase [column: Chiralcel AD-H, 5 μm, 250 mm×30 mm;mobile phase: carbon dioxide/isopropanol 88:12 (v/v); flow rate: 125g/min; pressure: 135 bar; UV detection: 210 nm; temperature: 38° C.]:

Example 76A (Enantiomer 1)

Yield: 274 mg

R_(t)=1.69 min; chemical purity >98%; >99% ee

[column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbondioxide/isopropanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar;UV detection: 210 nm; temperature: 60° C.].

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.36-1.46 (m, 9H), 1.49-1.62 (m,1.5H), 1.62-1.84 (m, 1.5H), 1.84-2.30 (m, 3H), 2.76-3.00 (m, 1H),3.05-3.44 (m, 1H), 3.65-3.95 (m, 5H), 4.49-4.81 (m, 2H), 6.94 (dd, 1H),7.20-7.42 (m, 1H), 7.69-7.90 (m, 1H).

LC-MS (method 1): R_(t)=0.97 min; m/z=362 (M+H)⁺.

Example 77A (Enantiomer 2)

Yield: 273 mg

R_(t)=1.82 min; chemical purity >96%; >92% ee

[column: Chiralpak AD-3, 3 μm, 100 mm×4.6 mm; mobile phase: carbondioxide/isopropanol 85:15 (v/v); flow rate: 3 ml/min; pressure: 130 bar;UV detection: 210 nm; temperature: 60° C.].

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.33-1.47 (m, 9H), 1.48-1.63 (m,1.5H), 1.64-1.81 (m, 1.5H), 1.84-2.36 (m, 3H), 2.77-3.00 (m, 1H),3.04-3.45 (m, 1H), 3.68-3.98 (m, 5H), 4.50-4.81 (m, 2H), 6.94 (dd, 1H),7.20-7.45 (m, 1H), 7.82 (td, 1H).

LC-MS (method 2): R_(t)=1.90 min; m/z=362 (M+H)⁺.

Example 78A and Example 79A tert-Butyl9-(2-fluorobenzoyl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Enantiomers 1

1.27 g (3.65 mmol) of racemic tert-butyl9-(2-fluorobenzoyl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (Example64A) were separated into the enantiomers by preparative SFC-HPLC on achiral phase [column: Chiralpak OX-H, 5 μm, 250 mm×30 mm; mobile phase:carbon dioxide/isopropanol 85:15 (v/v); pressure: 120 bar; flow rate:120 g/min; UV detection: 210 nm; temperature: 38° C.]:

Example 78A (Enantiomer 1)

Yield: 628 mg

R_(t)=2.14 min; chemical purity >99%; >99% ee

[Aligent SFC; column: Chiralpak OX-3, 50 mm×4.6 mm; mobile phase: carbondioxide/isopropanol, gradient: 0 min 5% isopropanol, 0.5 min 5%isopropanol, 5 min 50% isopropanol, 6 min 50% isopropanol, 6.01 min 5%isopropanol, 7 min 5% isopropanol; flow rate: 3 ml/min; temperature: 40°C.; UV detection: 220 nm].

LC-MS (method 1): R_(t)=1.00 min; m/z=349 (M+H)⁺.

[α]_(D) ²⁰=−23.33° (c=0.41, methanol).

Example 79A (Enantiomer 2)

Yield: 602 mg

R_(t)=2.415 min; chemical purity >99%; >99% ee

[Aligent SFC; column: Chiralpak OX-3, 50 mm×4.6 mm; mobile phase: carbondioxide/isopropanol, gradient: 0 min 5% isopropanol, 0.5 min 5%isopropanol, 5 min 50% isopropanol, 6 min 50% isopropanol, 6.01 min 5%isopropanol, 7 min 5% isopropanol; flow rate: 3 ml/min; temperature: 40°C.; UV detection: 220 nm].

LC-MS (method 1): R_(t)=1.00 min; m/z=349 (M+H)⁺.

[α]_(D) ²⁰=+22.5° (c=0.41, methanol).

Example 80A 3,9-diazabicyclo[4.2.1]non-9-yl(2-fluorophenyl)methanone(Enantiomer 1)

With stirring, 4.5 ml of dioxane and 4.5 ml of a 4 M solution ofhydrogen chloride in dioxane were added to tert-butyl9-(2-fluorobenzoyl)-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (628 mg,1.80 mmol, enantiomer 1), and the mixture was stirred at roomtemperature overnight. The reaction mixture was then concentrated todryness and the residue was taken up in 10 ml of THF. 0.33 ml oftriethylamine was then added with stirring, and the mixture was stirredat room temperature for 1 h. The mixture was then diluted with water andethyl acetate. The organic phase was removed, washed with water, driedover magnesium sulfate and concentrated to dryness. This gave 153 mg(content 100%, 0.61 mmol, 40% of theory) of the title compound.

LC-MS (method 1): R_(t)=0.32 min; m/z=249 (M+H)⁺.

Analogously to Example 80A, the following compound was prepared from thestarting material stated:

Example Name/Structure/Starting material Analytical data 81A

LC-MS (method 1): R_(t) = 0.32 min; m/z = 249 (M + H)⁺.

Analogously to Examples 62A and 63A, the following compound was preparedfrom the starting material specified:

Example Name/Structure/Starting material Analytical data 82A

LC-MS (method 2): R_(t) = 0.49 min; m/z = 296 (M + H)⁺.

Analogously to Examples 55A, 60A and 61A, the following compounds wereprepared from the starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 83A

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] = 1.29-1.49 (m, 9H), 1.51-1.71 (m,3H), 1.72-1.95 (m, 1.25H), 2.18-2.29 (m, 0.25H), 2.30-2.42 (m, 0.75H),2.81-3.00 (m, 0.25H), 3.02-3.26 (m, 1H), 3.35-3.52 (m, 1.5H), 3.52-3.64(m, 1H), 3.79-3.89 (m, 3H), 3.90-4.22 (m, 2.75H), 4.57 (br. s, 0.25H),6.90 (d, 1H), 7.12- 7.26 (m, 1H), 7.75- 7.86 (m, 1H). LC-MS (method 1):R_(t) = 0.98 min; m/z = 362 (M + H)⁺. 84A

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] = 1.32-1.48 (m, 9H), 1.51-1.72 (m,3H), 1.72-1.93 (m, 1.25H), 2.20-2.28 (m, 0.25H), 2.30-2.42 (m, 0.75H),3.02-3.26 (m, 2H), 3.48 (br. d, 0.75H), 3.62 (br. d, 0.75H), 3.76-3.89(m, 3.75H), 3.90-4.23 (m, 2.25H), 4.56-4.68 (m, 0.25H), 6.91-6.99 (m,1H), 7.73-7.85 (m, 1H). LC-MS (method 1): R_(t) = 0.93 min; m/z = 380(M + H)⁺. 85A

LC-MS (method 1): R_(t) = 1.04 min; m/z = 396/398 (M + H)⁺.

Example 86A3,6-Diazabicyclo[3.2.2]non-6-yl(3-fluoro-6-methoxypyridin-2-yl)methanonehydrochloride (Enantiomer 1)

With stirring, 7 ml of a 4 M solution of hydrogen chloride in dioxanewere added to tert-butyl6-[(3-fluoro-6-methoxypyridin-2-yl)carbonyl]-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate(enantiomer 1) (1060 mg, 2.79 mmol). The mixture was stirred at roomtemperature overnight. The reaction solution was then concentrated todryness and the resulting residue was dried under high vacuum at 40° C.This gave 763 mg of the target product.

LC-MS (method 2): R_(t)=0.54 min; m/z=280 (M+H)⁺.

Analogously to Example 86A, the following compounds were prepared fromthe starting material specified in each case:

Example Name/Structure/Starting material Analytical data 87A

LC-MS (method 2): R_(t) = 0.54 min; m/z = 262 (M + H)⁺. 88A

LC-MS (method 1): R_(t) = 0.40 min; m/z = 296/298 (M + H)⁺.

Example 89A and Example 90A 9-Benzyl 3-tert-butyl3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate (Enantiomer 1 and 2)

135.7 g (376 mmol) of the racemic 9-benzyl 3-tert-butyl3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate (prepared according tothe original synthesis procedure US 20150132258) were separated into theenantiomers by preparative SFC-HPLC on a chiral phase (column: ChiralcelAZ, 20 m, 360 mm×50 mm; mobile phase: carbon dioxide/MeOH 90:10 (v/v);flow rate: 400 ml/min; pressure: 110 bar; UV detection: 210 nm;temperature: 40° C.]:

Example 89A (Enantiomer 1)

Yield: 57.7 g

R_(t)=1.92 min; chemical purity >×100%; >99% ee

[Column: Chiralpak AZ-H, 5 μm, 150 mm×4.6 mm; mobile phase: carbondioxide/methanol 90:10; flow rate: 3 ml/min; pressure: 130 bar; UVdetection: 210 nm; temperature: 40° C.].

LC-MS (Method 2): R_(t)=2.22 min; m/z=305 (M+H-C4H8)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33-1.45 (m, 9H), 1.49 (br s, 1H),1.57-1.75 (m, 2H), 1.81-2.07 (m, 2H), 2.14-2.34 (m, 1H), 2.57-2.84 (m,1H), 2.87-3.18 (m, 1H), 3.52-3.89 (m, 2H), 4.16-4.28 (m, 2H), 4.96-5.17(m, 2H), 7.24-7.46 (m, 5H).

Example 90A (Enantiomer 2)

Yield: 62.1 g

R_(t)=2.31 min; chemical purity >99%; >94% ee

[Column: Chiralpak AZ-H, 5 μm, 150 mm×4.6 mm; mobile phase: carbondioxide/methanol 90:10; flow rate: 3 ml/min; pressure: 130 bar; UVdetection: 210 nm; temperature: 40° C.].

LC-MS (Method 2): R_(t)=2.22 min; m/z=305 (M+H-C4H8)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33-1.44 (m, 9H), 1.48 (br s, 1H),1.55-1.74 (m, 2H), 1.78-2.06 (m, 2H), 2.12-2.32 (m, 1H), 2.56-2.86 (m,1H), 2.90-3.18 (m, 1H), 3.50-3.88 (m, 2H), 4.24 (br t, 2H), 4.98-5.18(m, 2H), 7.25-7.43 (m, 5H).

Example 91A tert-Butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Enantiomer 2)

9-Benzyl 3-tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate(Enantiomer 2) (62.0 g, 172 mmol) was initially charged in ethanol (500ml) and flushed with argon. Pd/C 5 mol % (3.66 g, 1.72 mmol) was thenadded and the mixture was stirred overnight at room temperature andunder a hydrogen atmosphere (1 bar). More Pd/C 5 mol % (3.66 g, 1.72mmol) was then added and the mixture was stirred at room temperature foranother 7 h (hydrogen 1 bar). The mixture was then filtered andconcentrated to dryness under reduced pressure. This gave 25.6 mg(content 100%, 157 mmol, 91% of theory) of the title compound.

GC-MS (Method 3): R_(t)=5.23, min; m/z=226 (M⁺)

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.24-1.34 (m, 1H), 1.39 (s, 9H),1.47-1.74 (m, 4H), 1.86-2.01 (m, 1H), 2.55-2.65 (br. s, 1H), 2.67-2.81(m, 1H), 2.97-3.16 (m, 1H), 3.35-3.45 (m, 1H), 3.49-3.59 (m, 1.5H),3.60-3.78 (m, 1.5H).

Example 92A tert-Butyl 3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Enantiomer 1)

9-Benzyl 3-tert-butyl 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylate(Enantiomer 1) (57.7 g, 160 mmol) was initially charged in ethanol (500ml) and flushed with argon. Pd/C 5 mol % (3.41 g, 1.60 mmol) was thenadded and the mixture was stirred overnight at room temperature andunder a hydrogen atmosphere (1 bar). Pd/C 5 mol % (3.41 g, 1.60 mmol)was then added and stirring of the mixture at room temperature wascontinued overnight (hydrogen 1 bar). The mixture was then filtered andconcentrated to dryness under reduced pressure. This gave 35.5 g(content 100%, 157 mmol, 98% of theory) of the title compound.

GC-MS (Method 3): R_(t)=5.24, min; m/z=226 (M⁺⁾

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.24-1.32 (m, 1H), 1.39 (s, 9H),1.47-1.73 (m, 4H), 1.84-2.01 (m, 1H), 2.67-2.82 (m, 1H), 2.96-3.17 (m,1H), 3.36-3.41 (m, 1H), 3.50-3.58 (m, 1.5H), 3.61-3.79 (m, 1.5H).

Analogously to Examples 55A, 60A and 61A, the following compounds wereprepared from the starting materials stated in each case:

Example Name/Structure/Starting material Analytical data 94A

1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.45 (m, 9H), 1.48-1.66 (m, 1.5H),1.67-2.25 (m, 4H), 2.29-2.41 (m, 0.5H), 2.75-3.26 (m, 2H), 3.80-3.87 (m,6H), 4.57-4.75 (m, 1H), 6.95 (dd, 1H), 7.91 (t, 1H) LC-MS (Method 1): Rt= 1.04 min; MS (ESIpos): m/z = 396 (M + H)⁺

Analogously to Example 86A, the following compounds were prepared fromthe starting material stated in each case:

Example Name/Structure/Starting material Analytical data  96A

LC-MS (Method 1): R_(t) = 0.37 min; MS (ESIpos): m/z = 280 (M + H)⁺  97A

LC-MS (Method 1): R_(t) = 0.38 min; MS (ESIpos): m/z = 262 (M + H)⁺  98A

LC-MS (Method 1): R_(t) = 0.41 min; MS (ESIpos): m/z = 262 (M + H)⁺  99A

LC-MS (Method 1): R_(t) = 0.46 min; MS (ESIpos): m/z = 296 (M + H)⁺ 100A

LC-MS (Method 1): R_(t) = 0.46 min; MS (ESIpos): m/z = 296 (M + H)⁺

WORKING EXAMPLES Example 1 tert-Butyl6-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,6-diazabicyclo[3.2.2]nonane-2-carboxylate(Enantiomer 2)

Under argon, 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde(1.00 g, 3.88 mmol), tert-butyl2,6-diazabicyclo[3.2.2]nonane-2-carboxylate (enantiomer 2; 1.05 g, 4.66mmol) and acetic acid (440 μl, 7.8 mmol) were initially charged in 26 mlof THF. Subsequently, sodium triacetoxyborohydride (1.23 g, 5.82 mmol)was added and the mixture was stirred at room temperature overnight. Thereaction mixture was then first diluted with saturated ammonium chloridesolution, and saturated sodium carbonate solution was then added. Theorganic phase was separated off and the aqueous phase was extracted withethyl acetate. The combined organic phases were dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure. Onsilica gel (mobile phase: dichloromethane/methanol 50:1), the residueobtained was separated into its components. This gave 1,056 g (content100%, 2.25 mmol, 58% of theory) of the title compound.

LC-MS (method 2): R_(t)=1.50 min; m/z=468/470 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23-1.46 (m, 10H), 1.52-1.99 (m,5H), 2.56-2.73 (m, 2H), 2.93-3.08 (m, 1H), 3.12-3.28 (m, 1H), 3.51-3.75(m, 1H), 3.94-4.14 (m, 1H), 4.22 (br. s, 2H), 7.11 (dd, 1H), 7.55 (d,2H), 7.89 (d, 2H), 8.58 (dd, 1H), 8.85-9.04 (m, 1H).

Analogously to Example 1, the following compounds were prepared from thestarting materials specified in each case:

Name/Structure/Starting materials Example Analytical data 2

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.65), 0.008 (1.51), 1.272(16.00), 1.360 (10.16), 1.393 (5.02), 1.599 (1.53), 1.629 (1.48), 1.784(1.07), 1.916 (0.99), 2.328 (0.91), 2.566 (0.99), 2.617 (1.38), 2.670(1.65), 2.970 (0.69), 3.029 (0.97), 3.209 (0.61), 3.636 (0.87), 3.990(1.03), 4.111 (0.73), 4.220 (4.73), 5.754 (2.55), 7.092 (3.52), 7.103(3.60), 7.109 (3.61), 7.120 (3.58), 7.537 (8.91), 7.558 (10.30), 7.881(7.18), 7.902 (6.41), 8.573 (3.56), 8.578 (4.01), 8.583 (3.80), 8.588(3.65), 8.947 (1.80). LC-MS (method 2): R_(t) = 1.52 min; m/z = 468/470(M + H)⁺. 3

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.44), −0.008 (4.22), 0.008(3.54), 0.146 (0.46), 1.234 (0.51), 1.316 (16.00), 1.390 (11.89), 1.568(0.98), 1.597 (0.86), 1.670 (1.53), 1.814 (0.82), 1.924 (0.77), 2.328(0.41), 2.680 (0.64), 2.711 (1.05), 2.749 (0.60), 2.859 (2.45), 2.888(1.71), 3.048 (1.40), 3.287 (1.03), 3.622 (1.09), 3.657 (0.92), 4.021(0.99), 4.123 (0.72), 4.515 (2.25), 4.550 (3.12), 4.676 (0.72), 4.719(1.20), 4.754 (0.73), 5.755 (0.55), 6.951 (1.59), 6.968 (3.23), 6.984(1.78), 7.311 (1.85), 7.314 (1.88), 7.334 (2.46), 7.337 (2.29), 7.351(2.05), 7.353 (1.96), 7.599 (4.37), 7.622 (3.69), 7.982 (3.36), 7.989(3.41), 8.004 (4.10), 8.010 (4.21), 8.193 (5.92), 8.215 (4.84), 8.411(2.13), 8.428 (2.11), 8.653 (3.32). LC-MS (method 2): R_(t) = 1.26 min;m/z = 468/470 (M + H)⁺. 4

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.68), 0.008 (0.80), 1.285(16.00), 1.365 (10.59), 1.419 (1.11), 1.597 (1.40), 1.659 (1.45), 1.762(1.01), 1.909 (0.91), 2.367 (0.70), 2.523 (1.33), 2.526 (1.26), 2.558(1.09), 2.561 (1.04), 2.563 (1.08), 2.587 (0.99), 2.615 (0.56), 2.655(1.28), 2.670 (0.97), 2.675 (0.89), 2.694 (0.94), 2.710 (1.16), 2.961(0.70), 3.015 (0.96), 3.170 (0.60), 3.203 (0.60), 3.236 (0.46), 3.643(0.85), 3.677 (0.51), 4.000 (1.02), 4.120 (0.73), 4.194 (4.78), 5.755(0.65), 6.932 (1.71), 6.949 (3.48), 6.966 (1.88), 7.277 (1.84), 7.280(1.96), 7.299 (2.53), 7.302 (2.46), 7.316 (2.03), 7.319 (2.05), 7.507(8.35), 7.524 (3.12), 7.528 (9.53), 7.579 (4.15), 7.602 (3.55), 7.855(6.76), 7.876 (6.10), 8.491 (1.21), 8.508 (1.88). LC-MS (method 2):R_(t) = 1.56 min; m/z = 467/469 (M + H)⁺. 5

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.76), 0.008 (1.74), 1.285(16.00), 1.365 (10.49), 1.597 (1.39), 1.662 (1.44), 1.764 (1.00), 1.903(0.88), 2.328 (0.41), 2.367 (0.44), 2.588 (0.96), 2.651 (1.32), 2.670(1.03), 2.690 (0.93), 2.710 (0.88), 2.963 (0.67), 3.014 (0.93), 3.171(0.60), 3.201 (0.59), 3.236 (0.47), 3.643 (0.84), 4.002 (1.00), 4.120(0.71), 4.194 (4.70), 6.933 (1.70), 6.950 (3.46), 6.966 (1.87), 7.280(1.96), 7.300 (2.49), 7.302 (2.39), 7.317 (2.05), 7.319 (2.03), 7.507(8.31), 7.528 (9.38), 7.579 (4.11), 7.602 (3.50), 7.855 (6.76), 7.876(6.04), 8.491 (1.19), 8.508 (1.85). LC-MS (method 1): R_(t) = 0.80 min;m/z = 467/469 (M + H)⁺. 6

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.48 (m, 16H), 1.53-1.84 (m,4H), 1.86-1.98 (m, 1H), 2.47-2.77 (m, 2H, partially covered by DMSOsignal), 2.88-3.09 (m, 2H), 3.12-3.29 (m, 1H), 3.56-3.73 (m, 1H),3.96-4.07 (m, 0.5H), 4.07-4.16 (m, 0.5H), 4.22 (br. s, 2H), 7.08 (dd,1H), 7.36 (d, 2H), 7.78 (br. d, 2H), 8.55 (dd, 1H), 8.86-8.97 (m, 1H).LC-MS (method 2): R_(t) = 1.60 min; m/z = 476 (M + H)⁺. [α]_(D) ²⁰ =−9.42° (c = 0.29, Methanol). 7

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.48 (m, 16H), 1.53-1.84 (m,4H), 1.86-1.98 (m, 1H), 2.47-2.77 (m, 2H, partially covered by DMSOsignal), 2.88-3.09 (m, 2H), 3.12-3.29 (m, 1H), 3.56-3.72 (m, 1H),3.96-4.07 (m, 0.5H), 4.07-4.16 (m, 0.5H), 4.22 (br. s, 2H), 7.08 (dd,1H), 7.36 (d, 2H), 7.78 (br. d, 2H), 8.55 (dd, 1H), 8.87-8.96 (m, 1H).LC-MS (method 2): R_(t) = 1.61 min; m/z = 476 (M + H)⁺. [α]_(D) ²⁰ =+9.49° (c = 0.33, Methanol).

Example 8 tert-Butyl9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(racemate)

Under argon and at room temperature, 1.465 g (5.52 mmol) of2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde weredissolved in 20 ml of THF, and 1.5 g (6.63 mmol) of tert-butyl3,9-diazabicyclo[4.2.1]nonane-3-carboxylate (racemate) and 0.63 ml(11.05 mmol) of acetic acid were added. Subsequently, 1.756 g (8.29mmol) of sodium triacetoxyborohydride were added in portions, and thereaction solution was stirred at room temperature overnight. Then waterwas gradually and carefully added dropwise (caution: evolution of gas),and subsequently ethyl acetate was added. The resulting organic phasewas removed and the aqueous phase was extracted twice with ethylacetate. The combined organic phases were washed with saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure on a rotary evaporator.The residue obtained was purified by column chromatography (BiotageIsolera, Biotage SNAP-KP-NH column; mobile phase: cyclohexane/ethylacetate gradient 2:1→1:1). This gave 1.75 g (content 96%, 3.53 mmol, 64%of theory) of the target compound.

LC-MS (method 2): R_(t)=2.06 min; m/z=476 (M+H)⁺.

Example 9 and Example 10 tert-Butyl9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Enantiomer 1 and 2)

1.75 g (3.68 mmol) of racemic tert-butyl9-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonane-3-carboxylate(Example 8) were separated into the enantiomers by preparative HPLC on achiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm×20 mm; mobilephase: isopropanol+0.2% diethylamine (v/v); flow rate: 15 ml/min; UVdetection: 220 nm; temperature: 40° C.]:

Example 9 (Enantiomer 1)

Yield: 745 mg

R_(t)=7.652 min; chemical purity >98.9%; >99% ee

[column: Daicel Chiralpak ID, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/isopropanol 50:50+0.2% diethylamine (v/v); flow rate: 1ml/min; temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 2): R_(t)=2.04 min; m/z=476 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 1.29-1.56 (m, 12H),1.56-1.67 (m, 1H), 1.92-2.07 (m, 1H), 2.14-2.28 (m, 1H), 2.79 (br. d,1H), 2.88-3.01 (m, 1.5H), 3.01-3.13 (m, 0.5H), 3.17-3.35 (m, 2H,partially covered by H₂O signal), 3.47 (br. d, 0.5H), 3.61 (br. d,1.5H), 4.16-4.30 (m, 2H), 7.05-7.14 (m, 1H), 7.37 (d, 2H), 7.79 (d, 2H),8.52-8.61 (m, 1H), 9.02-9.12 (m, 1H).

Example 10 (Enantiomer 2)

Yield: 751 mg

R_(t)=6.945 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak ID, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/isopropanol 50:50+0.2% diethylamine (v/v); flow rate: 1ml/min; temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 2): R_(t)=2.04 min; m/z=476 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25 (d, 6H), 1.29-1.56 (m, 12H),1.56-1.67 (m, 1H), 1.92-2.07 (m, 1H), 2.14-2.27 (m, 1H), 2.79 (br. d,1H), 2.88-3.01 (m, 1.5H), 3.01-3.12 (m, 0.5H), 3.17-3.35 (m, 2H,partially covered by H₂O signal), 3.47 (br. d, 0.5H), 3.61 (br. d,1.5H), 4.16-4.29 (m, 2H), 7.05-7.14 (m, 1H), 7.37 (d, 2H), 7.79 (d, 2H),8.53-8.61 (m, 1H), 9.03-9.12 (m, 1H).

Example 113-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 1)

Under argon, [2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methanol(2.48 g, 9.58 mmol) and triethylamine (10 ml, 72 mmol) were initiallycharged in 40 ml of dichloromethane. In an ice bath, the mixture wascooled to 0° C., and methanesulfonyl chloride (1.9 ml, 24 mmol) was thenadded slowly. The mixture was stirred in the ice bath for 30 min.(3-Fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone(2.36 g, 7.98 mmol, enantiomer 1) in 40 ml of acetonitrile was thenadded slowly. The reaction solution was then heated to 40° C. andstirred at this temperature for 2 h. The reaction mixture wassubsequently diluted with 1 N aqueous sodium hydroxide solution and theaqueous phase was extracted with ethyl acetate. The combined organicphases were dried over magnesium sulfate, filtered and concentrated. Onsilica gel (mobile phase: cyclohexane/ethyl acetate 5:2), the residueobtained was separated into its components. The mixed fraction obtainedwas then re-purified by preparative HPLC (Method 10). The productfractions obtained in this manner were taken up in ethyl acetate, andthe organic phase was washed with saturated sodium carbonate solution,dried over magnesium sulfate, filtered and once more concentrated todryness. This gave 3.00 g (content 100%, 5.58 mmol, 70% of theory) ofthe title compound.

LC-MS (method 2): R_(t)=1.44 min; m/z=536/538 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.47-1.65 (m, 1H), 1.72-1.88 (m, 1H),2.31-2.46 (m, 0.4H), 2.58-2.89 (m, 3H), 2.90-2.98 (m, 0.6H), 3.41 (dd,0.6H), 3.47-3.82 (m, 7.4H), 4.10-4.29 (m, 2H), 4.38-4.58 (m, 1H),6.83-7.02 (m, 2H), 7.22-7.36 (m, 1H), 7.45-7.54 (m, 2H), 7.55-7.63 (m,1H), 7.72-7.84 (m, 1H), 7.85-8.04 (m, 2H), 8.69-8.92 (m, 1H).

[α]_(D) ²⁰=−5.85° (c=0.410, methanol).

Example 123-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 2)

Under argon, [2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methanol(2.05 g, 7.91 mmol) and triethylamine (8.3 ml, 59 mmol) were initiallycharged in 40 ml of dichloromethane. In an ice bath, the mixture wascooled to 0° C., and methanesulfonyl chloride (1.5 ml, 20 mmol) was thenadded slowly. The mixture was stirred in the ice bath for 30 min.(3-Fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone(1.95 g, 6.59 mmol, enantiomer 2) in 40 ml of acetonitrile was thenadded slowly. The reaction solution was then heated to 40° C. andstirred at this temperature for 2 h. The reaction mixture wassubsequently diluted with 1 N aqueous sodium hydroxide solution and theaqueous phase was extracted with ethyl acetate. The combined organicphases were dried over magnesium sulfate, filtered and concentrated. Onsilica gel (mobile phase: cyclohexane/ethyl acetate 5:2), the residueobtained was separated into its components. The mixed fraction obtainedwas then re-purified by preparative HPLC (Method 10). The productfractions obtained in this manner were taken up in ethyl acetate, andthe organic phase was washed with saturated sodium carbonate solution,dried over magnesium sulfate, filtered and once more concentrated todryness. This gave 2.35 g (content 100%, 4.39 mmol, 67% of theory) ofthe title compound.

LC-MS (method 1): R_(t)=0.77 min; m/z=536/538 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.35-1.63 (m, 1H), 1.68-1.87 (m, 1H),2.31-2.46 (m, 0.4H), 2.58-2.88 (m, 3H), 2.89-3.02 (m, 0.6H), 3.41 (dd,0.6H), 3.46-3.86 (m, 7.4H), 4.07-4.30 (m, 2H), 4.40-4.57 (m, 1H),6.75-7.02 (m, 2H), 7.13-7.37 (m, 1H), 7.42-7.53 (m, 2H), 7.56-7.67 (m,1H), 7.72-7.83 (m, 1H), 7.84-8.04 (m, 2H), 8.62-8.94 (m, 1H).

[α]_(D) ²⁰=+8.10° (c=0.395, methanol).

Example 133-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 1)

Under argon, (3-fluoro-6-methoxypyridin-2-yl)[8-oxa-3,1-diazabicyclo[4.3.1]dec-10-yl]methanone (780 mg, 2.64 mmol,enantiomer 1), 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde(817 mg, 3.17 mmol) and acetic acid (360 μl, 6.3 mmol) were initiallycharged in 30 ml of THF. Sodium triacetoxyborohydride (1.01 g, 4.75mmol) was then added, and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was then diluted withsaturated sodium carbonate solution, the organic phase was removed andthe aqueous phase was extracted twice with ethyl acetate. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated to dryness. On neutral alumina (mobile phase:dichloromethane/methanol 50:1), the residue obtained was separated intoits components. 100 mg of the product obtained in this manner were thenre-purified by preparative HPLC (Method 9). This gave 81 mg (content100%, 0.150 mmol, 6% of theory) of the title compound.

LC-MS (method 2): R_(t)=1.65 min; m/z=537/539 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.47-1.66 (m, 1H), 1.73-1.88 (m, 1H),2.30-2.44 (m, 0.4H), 2.58-2.87 (m, 3H), 2.87-2.97 (m, 0.75H), 3.41 (dd,0.75H), 3.49-3.83 (m, 7.1H), 4.15-4.30 (m, 2H), 4.40-4.50 (m, 1H),6.91-6.99 (m, 1H), 7.01-7.08 (m, 1H), 7.54 (d, 2H), 7.73-7.85 (m, 1H),7.87-8.01 (m, 2H), 8.58 (dd, 1H), 9.15-9.36 (m, 1H).

Example 143-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 2)

Under argon,(3-fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone(575 mg, 1.95 mmol, enantiomer 2),2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde (602 mg, 2.34mmol) and acetic acid (270 μl, 4.7 mmol) were initially charged in 22 mlof THF. Sodium triacetoxyborohydride (743 mg, 3.50 mmol) was then added,and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was then diluted with saturated sodium carbonatesolution, the organic phase was removed and the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases weredried over magnesium sulfate, filtered and concentrated to dryness. Onneutral alumina (mobile phase: dichloromethane/methanol 50:1), theresidue obtained was separated into its components. 100 mg of theproduct obtained in this manner were then re-purified by preparativeHPLC (Method 9). This gave 85 mg (content 100%, 0.160 mmol, 8% oftheory) of the title compound.

LC-MS (method 2): R_(t)=1.65 min; m/z=537/539 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.50-1.62 (m, 1H), 1.70-1.88 (m, 1H),2.35-2.43 (m, 0.4H), 2.56-2.87 (m, 3H), 2.87-2.95 (m, 0.75H), 3.41 (dd,0.75H), 3.47-3.69 (m, 3.1H), 3.70-3.81 (m, 4H), 4.14-4.31 (m, 2H),4.39-4.50 (m, 1H), 6.89-7.00 (m, 1H), 7.01-7.12 (m, 1H), 7.49-7.59 (m,2H), 7.72-7.84 (m, 1H), 7.87-8.04 (m, 2H), 8.58 (dd, 1H), 9.10-9.38 (m,1H).

Example 15[3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 1)

Under argon,3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone(65.0 mg, 233 μmol, enantiomer 1),2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (50.0 mg,194 μmol) and acetic acid (22 μl, 390 μmol) were initially charged in1.2 ml of THF. Sodium triacetoxyborohydride (62 mg, 291 μmol) was thenadded, and the mixture was stirred at room temperature overnight.Thereafter, methanol was added and the reaction mixture was separateddirectly into its components via preparative HPLC (Method 9). This gave79 mg (100% pure, 0.151 mmol, 78% of theory) of the title compound.

LC-MS (method 2): R_(t)=1.22 min; m/z=521/523 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21-1.37 (m, 1H), 1.42-1.51 (m,0.5H), 1.50-1.59 (m, 0.5H), 1.59-1.69 (m, 1H), 1.70-1.90 (m, 1.5H),1.90-2.05 (m, 1H), 2.08-2.17 (m, 0.5H), 2.35-2.70 (m, 3H), 2.81-3.05 (m,1H), 3.74-3.83 (m, 3H), 3.84-3.90 (m, 1H), 4.39-4.60 (m, 2H), 4.68 (dd,1H), 6.94 (ddd, 1H), 7.01 (qd, 1H), 7.30-7.41 (m, 1H), 7.62 (ddt, 1H),7.77 (dt, 1H), 8.00 (td, 1H), 8.21 (td, 1H), 8.59 (dd, 1H), 8.62-8.71(m, 1H).

Example 16[3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 2)

Under argon,3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone(65.0 mg, 233 μmol, enantiomer 2),2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (50.0 mg,194 μmol) and acetic acid (22 μl, 390 μmol) were initially charged in1.2 ml of THF. Sodium triacetoxyborohydride (62 mg, 291 μmol) was thenadded, and the mixture was stirred at room temperature overnight.Thereafter, methanol was added and the reaction mixture was separateddirectly into its components via preparative HPLC (Method 9). This gave80 mg (100% pure, 0.154 mmol, 79% of theory) of the title compound.

LC-MS (method 2): R_(t)=1.23 min; m/z=521/523 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.23-1.37 (m, 1H), 1.41-1.50 (m,0.5H), 1.51-1.59 (m, 0.5H), 1.58-1.69 (m, 1H), 1.71-1.88 (m, 1.5H),1.89-2.06 (m, 1H), 2.06-2.19 (m, 0.5H), 2.35-2.46 (dt, 3H), 2.84-3.03(m, 1H), 3.74-3.83 (m, 3H), 3.84-3.90 (m, 1H), 4.36-4.59 (m, 2H), 4.68(dd, 1H), 6.93 (ddd, 1H), 7.01 (qd, 1H), 7.27-7.42 (m, 1H), 7.62 (dtt,1H), 7.77 (dt, 1H), 8.00 (td, 1H), 8.21 (td, 1H), 8.59 (dd, 1H),8.62-8.74 (m, 1H).

Example 17[6-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,6-diazabicyclo[3.2.2]non-2-yl](3-fluoro-6-methoxypyridin-2-yl)methanone(Enantiomer 2)

2-(4-Chlorophenyl)-3-(2,6-diazabicyclo[3.2.2]non-6-ylmethyl)imidazo[1,2-a]pyrimidinebis(trifluoroacetic acid) salt (enantiomer 2; 153 mg, 141 μmol),3-fluoro-6-methoxypyridine-2-carboxylic acid (29.0 mg, 169 μmol) and1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium3-oxide hexafluorophosphate (69.8 mg, 184 μmol) were dissolved in 1.7 mlof DMF. N-Ethyl-N-isopropylpropan-2-amine (170 μl, 990 μmol) was thenadded. The mixture was stirred at room temperature overnight.Thereafter, methanol was added and the reaction mixture was separateddirectly into its components via preparative HPLC (Method 9). This gave58.5 mg (100% pure, 0.112 mmol, 80% of theory) of the title compound.

LC-MS (method 2): R_(t)=1.40 min; m/z=521/523 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.33-1.48 (m, 0.6H), 1.59-1.93 (m,4.4H), 1.93-2.11 (m, 1H), 2.58-2.80 (m, 1.6H), 2.93 (br. d, 0.6H),2.98-3.16 (m, 1H), 3.24-3.41 (m, 1.4H), 3.60 (s, 1.2H), 3.70 (br. s,0.4H), 3.78 (s, 1.8H), 4.04-4.16 (m, 0.4H), 4.20-4.37 (m, 2H), 4.57 (br.s, 0.6H), 6.81-6.99 (m, 1H), 7.11 (dd, 1H), 7.49-7.59 (m, 2H), 7.66-7.83(m, 1H), 7.85-7.98 (m, 2H), 8.53-8.63 (m, 1H), 8.94-9.03 (m, 1H).

Analogously to Example 17, the following compounds were prepared fromthe starting materials specified in each case:

Name/Structure/Starting materials Example Analytical data 18

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37-1.53 (m, 0.3H), 1.56-2.12 (m,5.7H), 2.71-2.87 (m, 1H), 2.96 (br. d, 0.4H), 3.03-3.20 (m, 1.6H),3.33-3.55 (m, 1.4H), 3.61 (s, 1.2H), 3.85 (s, 1.8H), 3.87-3.93 (m,0.6H), 4.00-4.11 (m, 0.4H), 4.49-4.73 (m, 2H), 4.82 (d, 0.6H), 6.77-6.94(m, 1H), 6.93-7.15 (m, 2H), 7.27- 7.40 (m, 1H), 7.62 (br. d, 1H),7.68-7.88 (m, 1H), 7.93-8.09 (m, 1H), 8.21 (d, 1H), 8.46 (d, 1H),8.53-8.72 (m, 1H). LC-MS (method 2): R_(t) = 1.16 min; m/z = 503/505(M + H)⁺. 19

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37-1.48 (m, 0.7H), 1.56-2.11 (m,5.3H), 2.69-2.94 (m, 1.6H), 3.03-3.20 (m, 1.8H), 3.32-3.48 (m, 1.2H),3.61 (s, 1H), 3.71 (br. s, 0.4H), 3.83 (s, 2H), 4.08 (dt, 0.3H),4.49-4.74 (m, 2H), 4.81 (d, 0.7H), 6.77-7.05 (m, 2H), 7.20-7.41 (m, 1H),7.57-7.66 (m, 1H), 7.66-7.86 (m, 1H), 7.90-8.04 (m, 1H), 8.21 (d, 1H),8.45 (d, 1H), 8.54-8.71 (m, 1H). LC-MS (method 2): R_(t) = 1.11 min; m/z= 521/523 (M + H)⁺. 20

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.37-1.49 (m, 0.8H), 1.57-2.08 (m,5.2H), 2.63-2.93 (m, 1.6H), 3.03-3.26 (m, 2.7H), 3.35-3.48 (m, 0.4H),3.56 (br. s, 0.3H), 3.64 (s, 1H), 3.84 (s, 2H), 4.05-4.15 (m, 0.3H),4.51-4.62 (m, 1.7H), 4.66- 4.84 (m, 1H), 6.80-7.04 (m, 2H), 7.29-7.39(m, 1H), 7.58-7.69 (m, 1H), 7.76-7.95 (m, 1H), 8.00 (dd, 1H), 8.21 (d,1H), 8.45 (d, 1H), 8.56-8.74 (m, 1H). LC-MS (method 2): R_(t) = 1.19min; m/z = 537/539 (M + H)⁺. 21

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36-1.49 (m, 0.6H), 1.57-2.13 (m,5.4H), 2.62-2.85 (m, 1.6H), 2.90 (br. d, 0.6H), 3.03 (br. d, 0.6H), 3.14(br. s, 0.4H), 3.22-3.40 (m, 0.8H), 3.42-3.52 (m, 0.6H), 3.58 (s, 1.3H),3.80 (s, 1.7H), 3.88 (br. s, 0.4H), 4.08 (dt, 0.4H), 4.18-4.37 (m, 2H),4.56 (br. s, 0.6H), 6.70-6.92 (m, 1H), 6.96-7.16 (m, 2H), 7.42-7.61 (m,2H), 7.68-7.85 (m, 1H), 7.86-7.99 (m, 2H), 8.58 (td, 1H), 9.01 (ddd,1H). LC-MS (method 2): R_(t) = 1.28 min; m/z = 503/505 (M + H)⁺. 22

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.45), −0.008 (3.62), 0.008(3.77), 1.355 (1.77), 1.367 (1.97), 1.378 (1.57), 1.389 (2.27), 1.401(2.12), 1.558 (0.70), 1.570 (0.82), 1.596 (1.85), 1.622 (2.85), 1.652(4.27), 1.731 (2.00), 1.756 (2.70), 1.767 (2.77), 1.795 (3.50), 1.805(3.15), 1.948 (1.70), 1.979 (2.37), 2.073 (2.50), 2.328 (0.95), 2.366(0.70), 2.585 (1.45), 2.670 (1.25), 2.716 (2.20), 2.726 (2.42), 2.745(3.12), 2.755 (2.90), 2.888 (3.85), 2.916 (2.85), 2.975 (3.32), 3.063(1.10), 3.260 (4.75), 3.653 (1.20), 4.098 (0.52), 4.196 (5.40), 4.232(0.85), 4.270 (16.00), 4.308 (0.57), 4.598 (3.52), 5.754 (1.20), 7.105(2.05), 7.122 (4.47), 7.133 (5.02), 7.148 (3.20), 7.197 (2.10), 7.219(2.30), 7.243 (1.90), 7.270 (5.72), 7.289 (7.35), 7.312 (3.37), 7.393(0.63), 7.406 (0.97), 7.414 (1.17), 7.427 (1.12), 7.454 (1.65), 7.468(2.42), 7.475 (2.65), 7.489 (2.80), 7.498 (1.67), 7.511 (1.10), 7.546(11.40), 7.562 (9.30), 7.567 (14.40), 7.583 (5.00), 7.898 (10.60), 7.901(10.70), 7.919 (10.67), 8.572 (2.07), 8.577 (2.35), 8.587 (7.40), 8.592(6.20), 8.597 (5.85), 8.602 (5.40), 8.963 (2.07), 8.968 (2.20), 8.985(4.55), 9.004 (3.10). LC-MS (method 2): R_(t) = 1.39 min; m/z = 490/492(M + H)⁺. 23

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.27), 0.008 (1.34), 1.405(0.51), 1.416 (0.57), 1.429 (0.45), 1.440 (0.65), 1.451 (0.58), 1.614(0.50), 1.625 (0.62), 1.648 (1.06), 1.679 (1.30), 1.756 (0.50), 1.766(0.55), 1.794 (0.86), 1.807 (1.03), 1.819 (0.96), 1.843 (0.91), 1.970(0.48), 2.002 (0.74), 2.074 (0.44), 2.566 (0.41), 2.583 (0.57), 2.594(0.52), 2.642 (0.68), 2.671 (0.67), 2.714 (0.74), 2.723 (0.78), 2.743(1.09), 2.753 (0.99), 2.844 (1.12), 2.873 (0.74), 3.040 (0.94), 3.127(0.80), 3.149 (0.76), 3.163 (1.05), 3.179 (0.80), 3.191 (0.68), 3.202(0.62), 3.215 (0.71), 3.540 (0.53), 3.623 (5.48), 3.798 (16.00), 4.234(2.53), 4.274 (2.71), 4.285 (2.72), 4.321 (0.46), 4.563 (1.13), 6.829(1.52), 6.851 (1.61), 6.902 (3.28), 6.924 (3.42), 7.099 (2.02), 7.109(2.12), 7.116 (2.10), 7.126 (2.07), 7.523 (3.92), 7.544 (6.35), 7.566(2.14), 7.789 (1.55), 7.811 (1.49), 7.869 (3.53), 7.878 (4.61), 7.891(3.62), 7.899 (4.20), 7.908 (2.41), 7.930 (1.90), 8.567 (0.74), 8.572(0.85), 8.577 (0.85), 8.585 (1.77), 8.590 (1.78), 8.595 (1.67), 8.600(1.60), 8.968 (1.48), 8.973 (1.54), 8.986 (1.85), 8.990 (1.90), 9.005(0.73), 9.009 (0.69). LC-MS (method 1): R_(t) = 0.75 min; m/z = 537/539(M + H)⁺. 24

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.41-1.69 (m, 2H), 1.72-2.05 (m,4H), 2.70-2.85 (m, 1.4H), 2.91-3.10 (m, 1.6H), 3.38-3.60 (m, 1H), 3.71(dt, 0.6H), 3.96-4.07 (m, 0.4H), 4.16 (br. s, 0.4H), 4.24 (d, 2H), 4.59(br. s, 0.6H), 6.31 (br. d, 2H), 7.01-7.13 (m, 1H), 7.42-7.63 (m, 2H),7.82-7.98 (m, 2H), 8.58 (dd, 1H), 9.00 (dd, 1H). LC-MS (method 2): R_(t)= 1.25 min; m/z = 479/481 (M + H)⁺. 25

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (1.11), −0.008 (9.05), 0.008(8.48), 0.146 (1.05), 1.345 (1.96), 1.356 (2.14), 1.379 (2.51), 1.390(2.31), 1.563 (0.94), 1.600 (2.11), 1.626 (2.99), 1.656 (4.84), 1.773(2.76), 1.800 (4.30), 1.945 (1.94), 1.975 (2.56), 2.073 (2.48), 2.328(1.88), 2.367 (0.88), 2.603 (1.40), 2.670 (2.16), 2.711 (1.31), 2.733(2.08), 2.756 (2.59), 2.911 (4.33), 2.940 (3.25), 2.970 (3.81), 3.059(1.14), 3.260 (4.95), 3.661 (1.31), 4.171 (6.80), 4.206 (1.31), 4.242(9.00), 4.250 (11.27), 4.286 (1.40), 4.604 (3.67), 5.755 (0.63), 6.951(1.34), 6.968 (4.81), 6.984 (5.98), 7.001 (2.76), 7.203 (2.28), 7.226(2.51), 7.249 (2.85), 7.270 (6.52), 7.291 (10.65), 7.314 (8.34), 7.331(4.75), 7.417 (1.28), 7.431 (1.14), 7.453 (2.11), 7.467 (2.56), 7.475(2.99), 7.488 (3.07), 7.516 (12.44), 7.537 (16.00), 7.554 (5.75), 7.577(3.10), 7.589 (8.00), 7.600 (2.79), 7.611 (6.78), 7.871 (9.59), 7.877(13.04), 7.893 (10.51), 7.898 (10.88), 8.524 (2.45), 8.541 (2.70), 8.553(4.90), 8.571 (4.70). LC-MS (method 1): R_(t) = 0.73 min; m/z = 489/491(M + H)⁺. 26

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (2.10), 0.008 (2.26), 1.396(0.45), 1.407 (0.51), 1.431 (0.57), 1.442 (0.55), 1.611 (0.44), 1.636(0.92), 1.648 (0.85), 1.662 (1.28), 1.694 (1.28), 1.727 (0.53), 1.765(0.55), 1.792 (0.46), 1.864 (1.08), 1.994 (0.51), 2.073 (2.51), 2.328(0.51), 2.653 (0.45), 2.666 (0.86), 2.682 (0.71), 2.695 (0.62), 2.711(1.07), 2.720 (0.80), 2.740 (0.97), 2.749 (0.88), 2.793 (0.80), 2.822(0.54), 2.916 (1.00), 2.944 (0.76), 3.018 (0.84), 3.135 (0.61), 3.339(0.97), 3.352 (0.52), 3.363 (0.53), 3.450 (0.83), 3.463 (0.47), 3.486(0.51), 3.589 (10.16), 3.794 (16.00), 3.894 (0.72), 4.063 (0.49), 4.098(0.45), 4.207 (1.33), 4.217 (3.00), 4.243 (2.05), 4.289 (2.03), 4.326(0.92), 4.573 (0.98), 6.794 (1.43), 6.815 (1.47), 6.873 (2.08), 6.893(2.15), 6.944 (1.18), 6.961 (2.39), 6.978 (1.30), 6.996 (1.43), 7.014(1.47), 7.039 (2.09), 7.057 (2.13), 7.279 (0.69), 7.283 (0.90), 7.286(0.91), 7.301 (1.52), 7.318 (0.72), 7.323 (0.93), 7.462 (3.80), 7.483(4.27), 7.523 (2.58), 7.545 (2.88), 7.583 (1.80), 7.585 (1.99), 7.608(1.68), 7.703 (1.13), 7.721 (1.24), 7.724 (1.27), 7.742 (1.03), 7.779(1.65), 7.798 (1.82), 7.800 (1.86), 7.819 (1.51), 7.869 (4.32), 7.890(3.96), 7.902 (3.04), 7.923 (2.60), 8.557 (1.62), 8.574 (1.88), 8.587(1.08). LC-MS (method 1): R_(t) = 0.70 min; m/z = 502/504 (M + H)⁺. 27

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.34-1.47 (m, 0.6H), 1.57-2.05 (m,5.4H), 2.61-2.79 (m, 1.5H), 2.96 (br. d, 0.6H), 2.99-3.15 (m, 1H),3.25-3.40 (m, 1.5H), 3.60 (s, 1.1H), 3.71 (br. s, 0.4H), 3.78 (s, 1.9H),4.11 (dt, 0.4H), 4.18-4.33 (m, 2H), 4.58 (br. s, 0.6H), 6.81-7.01 (m,2H), 7.19-7.38 (m, 1H), 7.46-7.55 (m, 2H), 7.56-7.63 (m, 1H), 7.68-7.83(m, 1H), 7.85-7.95 (m, 2H), 8.47-8.63 (m, 1H). LC-MS (method 1): R_(t) =0.73 min; m/z = 520/522 (M + H)⁺. 28

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (2.32), 0.008 (2.30), 1.396(0.46), 1.407 (0.53), 1.418 (0.41), 1.431 (0.59), 1.443 (0.56), 1.618(0.47), 1.629 (0.51), 1.652 (0.98), 1.679 (1.19), 1.764 (0.46), 1.773(0.53), 1.815 (1.01), 1.843 (0.82), 1.963 (0.47), 1.994 (0.67), 2.073(0.77), 2.328 (0.49), 2.600 (0.54), 2.612 (0.45), 2.675 (0.94), 2.710(0.56), 2.721 (0.67), 2.731 (0.75), 2.750 (1.01), 2.760 (0.88), 2.872(1.05), 2.901 (0.73), 3.033 (0.85), 3.125 (0.68), 3.147 (0.55), 3.161(0.95), 3.182 (0.57), 3.194 (0.63), 3.205 (0.56), 3.217 (0.65), 3.553(0.49), 3.632 (5.46), 3.798 (16.00), 4.206 (3.17), 4.242 (2.22), 4.266(2.24), 4.302 (0.70), 4.573 (1.05), 5.754 (1.12), 6.831 (1.54), 6.853(1.63), 6.900 (3.32), 6.923 (3.45), 6.940 (1.19), 6.957 (2.40), 6.974(1.30), 7.274 (0.44), 7.288 (1.25), 7.291 (1.31), 7.311 (1.50), 7.313(1.48), 7.328 (0.93), 7.330 (0.93), 7.493 (3.95), 7.498 (1.31), 7.514(6.19), 7.535 (2.12), 7.573 (0.94), 7.588 (1.91), 7.596 (0.84), 7.610(1.59), 7.794 (1.57), 7.816 (1.54), 7.854 (4.54), 7.858 (1.49), 7.868(3.83), 7.875 (4.11), 7.886 (2.47), 7.890 (3.92), 7.907 (1.88), 8.533(1.62), 8.550 (1.75), 8.573 (0.73). LC-MS (method 1): R_(t) = 0.77 min;m/z = 536/538 (M + H)⁺. 29

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.43-1.70 (m, 2H), 1.73-2.04 (m,4H), 2.73-2.86 (m, 1.4H), 2.91-3.08 (m, 1.6H), 3.37-3.59 (m, 1H), 3.71(dt, 0.6H), 4.02 (dt, 0.4H), 4.13-4.29 (m, 2.4H), 4.61 (br. s, 0.6H),6.32 (br. d, 2H), 6.82-7.06 (m, 1H), 7.20-7.39 (m, 1H), 7.44-7.63 (m,3H), 7.89 (dd, 2H), 8.56 (d, 1H). LC-MS (method 2): R_(t) = 1.31 min;m/z = 478/480 (M + H)⁺. 30

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.120 (0.50), 0.116 (0.46), 1.034(0.99), 1.045 (0.95), 1.231 (2.16), 1.360 (3.32), 1.369 (3.61), 1.378(2.86), 1.387 (3.85), 1.397 (3.61), 1.590 (3.19), 1.619 (4.68), 1.638(3.15), 1.673 (2.69), 1.778 (3.90), 1.801 (4.19), 1.848 (5.72), 1.906(2.20), 1.979 (3.40), 2.003 (3.85), 2.362 (1.49), 2.636 (1.45), 2.756(1.78), 2.850 (3.61), 2.867 (4.19), 3.076 (12.19), 3.100 (7.09), 3.448(0.95), 3.677 (2.07), 4.067 (0.66), 4.553 (3.52), 4.595 (11.03), 4.611(6.92), 4.755 (4.93), 4.782 (3.77), 6.968 (1.82), 6.982 (3.90), 6.995(5.06), 7.007 (5.93), 7.019 (3.52), 7.213 (2.16), 7.231 (3.32), 7.250(2.90), 7.317 (6.92), 7.333 (13.26), 7.349 (16.00), 7.363 (8.79), 7.420(1.91), 7.435 (1.82), 7.486 (4.89), 7.498 (4.77), 7.601 (4.52), 7.611(11.52), 7.619 (4.48), 7.629 (9.82), 7.986 (8.54), 7.991 (8.87), 7.996(4.10), 8.003 (11.44), 8.008 (10.49), 8.013 (4.06), 8.019 (3.40), 8.192(5.39), 8.203 (13.89), 8.209 (5.72), 8.220 (11.52), 8.422 (3.15), 8.437(3.19), 8.455 (9.87), 8.468 (9.37), 8.635 (9.08), 8.687 (4.44), 8.691(4.35). LC-MS (method 1): R_(t) = 0.66 min; m/z = 490/492 (M + H)⁺. 31

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.150 (0.47), −0.008 (4.05), 0.008(4.47), 0.146 (0.53), 1.355 (1.74), 1.367 (2.00), 1.378 (1.53), 1.389(2.32), 1.401 (2.21), 1.621 (2.84), 1.653 (4.16), 1.756 (2.74), 1.766(2.74), 1.795 (3.53), 1.947 (1.63), 1.980 (2.37), 1.988 (2.47), 2.073(4.79), 2.328 (1.63), 2.367 (0.84), 2.670 (1.89), 2.716 (2.21), 2.726(2.47), 2.746 (3.16), 2.755 (2.84), 2.887 (3.89), 2.917 (2.89), 2.985(3.32), 3.063 (1.11), 3.261 (5.00), 3.652 (1.26), 4.101 (0.53), 4.196(5.37), 4.232 (0.89), 4.271 (16.00), 4.308 (0.63), 4.597 (3.53), 5.754(0.47), 7.106 (2.16), 7.122 (4.53), 7.133 (5.11), 7.148 (3.21), 7.198(2.16), 7.219 (2.21), 7.243 (1.95), 7.270 (5.68), 7.289 (7.37), 7.312(3.42), 7.407 (1.11), 7.414 (1.16), 7.428 (1.16), 7.454 (1.84), 7.468(2.53), 7.476 (2.74), 7.489 (2.79), 7.498 (1.79), 7.511 (1.21), 7.546(11.79), 7.562 (9.37), 7.567 (14.89), 7.583 (5.21), 7.898 (10.68), 7.901(10.79), 7.919 (10.68), 8.572 (2.16), 8.577 (2.53), 8.587 (7.84), 8.592(6.58), 8.597 (6.21), 8.602 (5.74), 8.963 (2.11), 8.968 (2.21), 8.985(4.58), 9.005 (3.11). LC-MS (method 2): R_(t) = 1.41 min; m/z = 490/492(M + H)⁺. 32

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.33-1.50 (m, 0.6H), 1.58-2.12 (m,5.4H), 2.60-2.84 (m, 1.6H), 2.90 (br. d, 0.6H), 3.03 (br. d, 0.6H), 3.14(br. s, 0.4H), 3.23-3.40 (m, 0.8H), 3.42-3.53 (m, 0.6H), 3.58 (s,1.25H), 3.80 (s, 1.75H), 3.88 (br. s, 0.4H), 4.00-4.13 (m, 0.4H),4.17-4.38 (m, 2H), 4.56 (br. s, 1.6H), 6.74-6.94 (m, 1H), 6.97-7.22 (m,2H), 7.43-7.63 (m, 2H), 7.66-7.85 (m, 1H), 7.86-7.99 (m, 2H), 8.53-8.65(m, 1H), 9.01 (ddd, 1H). LC-MS (method 2): R_(t) = 1.30 min; m/z =503/505 (M + H)⁺. 33

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.18), 0.008 (1.18), 1.393(0.49), 1.405 (0.56), 1.416 (0.44), 1.428 (0.65), 1.439 (0.61), 1.615(0.65), 1.639 (1.17), 1.672 (1.48), 1.684 (1.31), 1.771 (0.74), 1.798(0.98), 1.830 (0.85), 1.851 (0.70), 1.901 (0.43), 1.975 (0.53), 2.006(0.82), 2.073 (2.43), 2.615 (0.40), 2.631 (0.72), 2.644 (0.67), 2.670(0.50), 2.687 (0.92), 2.717 (1.20), 2.725 (0.93), 2.746 (1.07), 2.755(0.94), 2.916 (1.10), 2.946 (0.83), 3.022 (0.96), 3.121 (0.60), 3.276(1.37), 3.293 (2.27), 3.343 (0.70), 3.594 (9.37), 3.695 (0.70), 3.783(16.00), 4.092 (0.48), 4.127 (0.45), 4.230 (4.17), 4.267 (2.36), 4.297(2.33), 4.333 (0.84), 4.567 (1.14), 6.850 (0.78), 6.858 (0.79), 6.873(0.89), 6.881 (0.85), 6.928 (1.26), 6.935 (1.29), 6.950 (1.45), 6.958(1.40), 7.097 (1.77), 7.107 (1.90), 7.114 (1.94), 7.124 (1.86), 7.513(3.82), 7.535 (4.30), 7.547 (2.43), 7.568 (2.63), 7.683 (0.84), 7.705(1.42), 7.727 (0.82), 7.766 (1.37), 7.788 (2.24), 7.809 (1.31), 7.889(4.49), 7.911 (4.36), 7.917 (3.30), 7.938 (2.43), 8.569 (0.93), 8.574(1.06), 8.583 (2.29), 8.587 (1.80), 8.593 (1.62), 8.598 (1.49), 8.977(1.46), 8.982 (1.53), 8.995 (2.11), 8.999 (2.10), 9.013 (0.94), 9.018(0.87). LC-MS (method 2): R_(t) = 1.41 min; m/z = 521/523 (M + H)⁺. 34

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.24), 0.008 (1.35), 1.405(0.46), 1.416 (0.53), 1.427 (0.40), 1.439 (0.60), 1.451 (0.56), 1.624(0.60), 1.648 (0.96), 1.677 (1.24), 1.755 (0.49), 1.765 (0.51), 1.807(0.97), 1.842 (0.85), 1.970 (0.46), 2.000 (0.70), 2.328 (0.47), 2.582(0.51), 2.594 (0.47), 2.641 (0.63), 2.670 (0.81), 2.712 (0.72), 2.723(0.72), 2.742 (1.04), 2.752 (0.92), 2.844 (1.04), 2.872 (0.71), 3.039(0.89), 3.127 (0.77), 3.148 (0.72), 3.162 (1.02), 3.177 (0.75), 3.191(0.65), 3.202 (0.58), 3.214 (0.67), 3.538 (0.50), 3.622 (5.31), 3.797(16.00), 4.233 (2.41), 4.274 (2.59), 4.284 (2.60), 4.320 (0.45), 4.560(1.09), 6.828 (1.52), 6.850 (1.60), 6.902 (3.31), 6.924 (3.42), 7.098(1.96), 7.109 (2.03), 7.116 (2.06), 7.126 (2.02), 7.522 (3.95), 7.544(6.30), 7.565 (2.11), 7.789 (1.56), 7.811 (1.49), 7.868 (3.52), 7.877(4.58), 7.890 (3.60), 7.898 (4.13), 7.908 (2.35), 7.929 (1.85), 8.567(0.75), 8.572 (0.83), 8.577 (0.83), 8.585 (1.71), 8.590 (1.78), 8.595(1.70), 8.600 (1.57), 8.968 (1.46), 8.973 (1.52), 8.985 (1.82), 8.990(1.85), 9.004 (0.70), 9.009 (0.68). LC-MS (method 2): R_(t) = 1.55 min;m/z = 537/539 (M + H)⁺. 35

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (1.14), −0.008 (8.80), 0.008(8.65), 0.146 (1.08), 1.465 (0.97), 1.476 (1.11), 1.487 (0.91), 1.500(1.25), 1.511 (1.22), 1.557 (0.65), 1.570 (0.77), 1.604 (1.51), 1.633(1.77), 1.656 (1.28), 1.776 (2.62), 1.805 (1.48), 1.850 (2.02), 1.875(2.02), 1.946 (1.31), 1.978 (1.45), 2.073 (16.00), 2.328 (1.62), 2.366(0.68), 2.670 (1.77), 2.710 (0.83), 2.731 (1.57), 2.740 (1.71), 2.760(2.08), 2.769 (1.88), 2.807 (3.76), 2.813 (3.93), 2.932 (2.22), 2.961(1.65), 3.018 (1.99), 3.418 (0.68), 3.442 (1.02), 3.466 (0.71), 3.502(0.63), 3.514 (0.80), 3.525 (0.71), 3.538 (1.48), 3.551 (1.05), 3.561(1.11), 3.572 (0.80), 3.687 (1.82), 3.700 (1.00), 3.723 (1.28), 4.002(1.08), 4.038 (1.00), 4.156 (1.59), 4.227 (7.09), 4.258 (10.16), 4.594(2.19), 6.307 (7.12), 6.320 (5.69), 7.081 (3.02), 7.091 (3.13), 7.098(3.16), 7.108 (4.47), 7.117 (2.05), 7.124 (2.05), 7.134 (2.02), 7.527(7.97), 7.541 (6.23), 7.548 (9.79), 7.562 (6.01), 7.895 (9.42), 7.904(6.60), 7.911 (3.84), 7.916 (8.57), 7.926 (5.67), 8.576 (4.90), 8.581(5.38), 8.586 (5.18), 8.591 (4.87), 8.987 (4.47), 8.992 (3.73), 9.004(4.38). LC-MS (method 2): R_(t) = 1.26 min; m/z = 479/481 (M + H)⁺. 36

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.91), −0.008 (7.77), 0.008(7.45), 0.146 (0.86), 1.233 (0.55), 1.345 (2.00), 1.356 (2.23), 1.367(1.68), 1.379 (2.45), 1.391 (2.41), 1.562 (0.86), 1.600 (2.14), 1.624(3.05), 1.656 (4.82), 1.763 (2.59), 1.773 (2.82), 1.801 (4.27), 1.944(1.91), 1.975 (2.64), 2.073 (0.55), 2.328 (1.68), 2.366 (0.59), 2.601(1.23), 2.670 (1.82), 2.711 (1.00), 2.734 (2.09), 2.757 (2.50), 2.911(4.41), 2.940 (3.36), 2.969 (3.86), 3.054 (1.18), 3.260 (5.18), 3.663(1.27), 4.083 (0.59), 4.171 (6.91), 4.206 (1.32), 4.242 (9.14), 4.250(11.64), 4.286 (1.36), 4.604 (3.73), 6.950 (1.32), 6.967 (4.86), 6.984(6.14), 7.001 (2.73), 7.204 (2.27), 7.226 (2.59), 7.249 (2.86), 7.270(6.68), 7.291 (10.59), 7.314 (8.36), 7.333 (4.64), 7.409 (1.05), 7.417(1.27), 7.431 (1.23), 7.453 (2.09), 7.467 (2.73), 7.475 (2.95), 7.488(3.23), 7.497 (2.05), 7.516 (12.32), 7.537 (16.00), 7.554 (5.59), 7.577(3.09), 7.589 (7.82), 7.599 (2.86), 7.611 (6.68), 7.871 (9.55), 7.876(13.14), 7.893 (10.55), 7.898 (11.05), 8.524 (2.41), 8.541 (2.73), 8.553(5.00), 8.570 (4.77). LC-MS (method 2): R_(t) = 1.43 min; m/z = 489/491(M + H)⁺. 37

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.42), 0.146 (0.42), 1.396(0.57), 1.407 (0.59), 1.418 (0.48), 1.432 (0.67), 1.441 (0.65), 1.635(1.14), 1.662 (1.54), 1.694 (1.55), 1.726 (0.65), 1.761 (0.64), 1.791(0.56), 1.864 (1.35), 1.992 (0.64), 2.073 (0.61), 2.327 (0.71), 2.653(0.55), 2.665 (1.20), 2.681 (0.89), 2.695 (0.76), 2.710 (1.19), 2.720(0.95), 2.740 (1.14), 2.748 (1.06), 2.793 (1.02), 2.822 (0.68), 2.915(1.25), 2.944 (0.95), 3.017 (1.06), 3.137 (0.77), 3.338 (1.25), 3.363(0.71), 3.375 (0.51), 3.449 (0.97), 3.462 (0.57), 3.486 (0.59), 3.589(10.54), 3.794 (16.00), 3.893 (0.88), 4.063 (0.57), 4.098 (0.56), 4.216(3.51), 4.242 (2.30), 4.289 (2.26), 4.325 (1.03), 4.570 (1.25), 6.793(1.61), 6.814 (1.66), 6.871 (2.31), 6.892 (2.48), 6.943 (1.29), 6.960(2.65), 6.977 (1.46), 6.995 (1.65), 7.013 (1.76), 7.038 (2.43), 7.055(2.52), 7.283 (1.06), 7.300 (1.79), 7.315 (0.94), 7.323 (1.11), 7.461(3.84), 7.482 (4.24), 7.523 (2.64), 7.544 (2.93), 7.584 (2.27), 7.606(1.96), 7.702 (1.08), 7.722 (1.45), 7.741 (0.98), 7.779 (1.49), 7.798(2.09), 7.818 (1.41), 7.869 (4.48), 7.890 (4.13), 7.901 (3.28), 7.923(2.76), 8.557 (1.78), 8.573 (2.23), 8.586 (1.24). LC-MS (method 2):R_(t) = 1.35 min; m/z = 502/504 (M + H)⁺. 38

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.30-1.48 (m, 0.6H), 1.54-2.05 (m,5.4H), 2.60-2.82 (m, 1.6H), 2.89-3.16 (m, 1.6H), 3.21-3.42 (m, 1.4H),3.60 (s, 1.1H), 3.71 (br. s, 0.4H), 3.78 (s, 1.9H), 4.03-4.16 (m, 0.4H),4.17-4.36 (m, 2H), 4.58 (br. s, 0.6H), 6.81-7.08 (m, 2H), 7.16-7.36 (m,1H), 7.46-7.56 (m, 2H), 7.55- 7.64 (m, 1H), 7.66-7.83 (m, 1H), 7.83-7.95(m, 2H), 8.48-8.64 (m, 1H). LC-MS (method 2): R_(t) = 1.44 min; m/z =520/522 (M + H)⁺. 39

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (2.44), 0.008 (2.27), 1.396(0.53), 1.408 (0.60), 1.419 (0.47), 1.431 (0.67), 1.442 (0.62), 1.618(0.53), 1.629 (0.57), 1.652 (1.07), 1.678 (1.32), 1.764 (0.53), 1.774(0.61), 1.803 (1.18), 1.842 (0.95), 1.963 (0.51), 1.995 (0.78), 2.328(0.58), 2.600 (0.55), 2.612 (0.49), 2.675 (1.05), 2.710 (0.58), 2.722(0.73), 2.731 (0.81), 2.750 (1.12), 2.760 (1.00), 2.872 (1.16), 2.901(0.81), 3.040 (0.98), 3.125 (0.75), 3.148 (0.61), 3.161 (1.06), 3.181(0.63), 3.194 (0.68), 3.205 (0.61), 3.217 (0.73), 3.556 (0.52), 3.632(5.59), 3.798 (16.00), 4.206 (3.35), 4.242 (2.43), 4.266 (2.44), 4.302(0.76), 4.572 (1.18), 6.831 (1.41), 6.853 (1.48), 6.900 (3.11), 6.923(3.26), 6.940 (1.23), 6.957 (2.52), 6.974 (1.38), 7.274 (0.46), 7.291(1.41), 7.313 (1.62), 7.329 (1.00), 7.493 (3.98), 7.514 (6.24), 7.535(2.09), 7.573 (0.92), 7.588 (2.04), 7.596 (0.90), 7.610 (1.70), 7.794(1.45), 7.816 (1.39), 7.854 (4.57), 7.868 (3.74), 7.875 (4.21), 7.886(2.49), 7.890 (3.83), 7.907 (1.88), 8.533 (1.75), 8.551 (1.89), 8.573(0.78). LC-MS (method 2): R_(t) = 1.52 min; m/z = 536/538 (M + H)⁺. 40

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.43-1.69 (m, 2H), 1.70-2.03 (m,4H), 2.73-2.86 (m, 1.4H), 2.92-3.07 (m, 1.6H), 3.39-3.59 (m, 1H), 3.71(dt, 0.6H), 4.02 (dt, 0.4H), 4.10-4.32 (m, 2.4H), 4.60 (br. s, 0.6H),6.32 (br. d, 2H), 6.87-7.07 (m, 1H), 7.22-7.37 (m, 1H), 7.44-7.55 (m,2H), 7.59 (d, 1H), 7.89 (dd, 2H), 8.56 (d, 1H). LC-MS (method 2): R_(t)= 1.30 min; m/z = 478/480 (M + H)⁺. 41

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (dd, 6H), 1.41-1.53 (m, 0.6H),1.59-2.13 (m, 5.4H), 2.58-2.85 (m, 1.5H), 2.86-3.00 (m, 1.6H), 3.03-3.21(m, 1H), 3.23-3.40 (m, 0.9H), 3.49 (dt, 0.6H), 3.57 (s, 1.25H), 3.79 (s,1.75H), 3.88 (br. s, 0.4H), 4.09 (dt, 0.4H), 4.21-4.42 (m, 2H), 4.58(br. s, 0.6H), 6.73-6.92 (m, 1H), 6.94-7.14 (m, 2H), 7.24-7.43 (m, 2H),7.61-7.86 (m, 3H), 8.55 (td, 1H), 8.98 (dt, 1H). LC-MS (method 1): R_(t)= 0.72 min; m/z = 511 (M + H)⁺. 42

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.92), 0.008 (0.89), 1.224(11.24), 1.242 (16.00), 1.261 (7.98), 1.404 (0.42), 1.415 (0.49), 1.438(0.52), 1.450 (0.47), 1.627 (0.47), 1.638 (0.50), 1.662 (0.90), 1.685(1.25), 1.694 (1.29), 1.788 (0.46), 1.804 (0.52), 1.826 (0.85), 1.861(0.67), 1.992 (0.51), 2.009 (0.46), 2.023 (0.53), 2.524 (0.63), 2.638(0.52), 2.650 (0.47), 2.711 (0.84), 2.720 (0.72), 2.730 (0.77), 2.749(0.87), 2.759 (0.74), 2.915 (0.92), 2.933 (1.42), 2.950 (1.88), 2.967(0.81), 2.983 (0.84), 3.061 (0.75), 3.155 (0.46), 3.284 (1.02), 3.582(7.67), 3.698 (0.52), 3.777 (13.47), 4.238 (2.65), 4.267 (1.72), 4.314(1.71), 4.350 (0.80), 4.581 (0.88), 6.846 (0.66), 6.854 (0.67), 6.868(0.76), 6.877 (0.72), 6.928 (1.09), 6.936 (1.11), 6.950 (1.26), 6.958(1.22), 7.069 (1.30), 7.073 (1.01), 7.080 (1.39), 7.086 (1.52), 7.090(1.05), 7.097 (1.37), 7.100 (0.97), 7.316 (2.86), 7.337 (3.12), 7.360(1.73), 7.381 (1.90), 7.680 (0.70), 7.702 (1.15), 7.724 (0.67), 7.765(1.90), 7.769 (3.53), 7.789 (4.21), 7.795 (2.71), 7.809 (1.50), 7.816(1.87), 8.540 (0.77), 8.545 (0.87), 8.551 (0.96), 8.555 (1.91), 8.559(1.51), 8.565 (1.34), 8.570 (1.26), 8.951 (1.25), 8.957 (1.63), 8.963(0.93), 8.968 (1.33), 8.974 (1.55), 8.980 (0.76). LC-MS (method 1):R_(t) = 0.76 min; m/z = 529 (M + H)⁺. 43

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.19), 0.008 (0.97), 1.237(15.38), 1.243 (7.80), 1.254 (15.99), 1.260 (7.51), 1.409 (0.54), 1.419(0.54), 1.431 (0.41), 1.443 (0.60), 1.455 (0.54), 1.647 (0.54), 1.672(0.96), 1.691 (1.24), 1.780 (0.53), 1.808 (1.02), 1.820 (1.03), 1.843(0.86), 1.988 (0.52), 2.019 (0.61), 2.524 (0.77), 2.583 (0.43), 2.661(0.61), 2.670 (0.46), 2.718 (0.66), 2.728 (0.75), 2.747 (0.99), 2.757(0.87), 2.868 (1.04), 2.898 (0.78), 2.910 (0.50), 2.927 (1.02), 2.944(1.31), 2.962 (0.97), 3.087 (0.88), 3.124 (0.40), 3.148 (0.68), 3.160(1.25), 3.184 (0.63), 3.196 (0.60), 3.207 (0.56), 3.219 (0.68), 3.546(0.41), 3.608 (4.29), 3.793 (16.00), 4.240 (2.20), 4.271 (2.17), 4.299(2.16), 4.334 (0.77), 4.572 (1.05), 6.823 (1.36), 6.845 (1.39), 6.900(3.42), 6.922 (3.56), 7.072 (2.11), 7.082 (2.14), 7.089 (2.13), 7.099(2.13), 7.330 (3.44), 7.351 (4.00), 7.356 (2.05), 7.377 (1.55), 7.756(4.04), 7.776 (3.70), 7.785 (2.39), 7.807 (2.75), 7.854 (3.49), 7.877(3.29), 8.538 (0.63), 8.542 (0.72), 8.548 (0.71), 8.556 (1.69), 8.561(1.77), 8.567 (1.68), 8.572 (1.60), 8.941 (1.45), 8.946 (1.60), 8.958(1.63), 8.963 (1.51), 8.972 (0.62). LC-MS (method 1): R_(t) = 0.81 min;m/z = 545/547 (M + H)⁺. 44

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.83), 0.008 (0.75), 1.243(15.81), 1.260 (16.00), 1.435 (0.68), 1.446 (0.73), 1.457 (0.68), 1.470(0.87), 1.482 (1.00), 1.488 (1.10), 1.509 (1.23), 1.526 (1.52), 1.546(1.93), 1.556 (1.63), 1.566 (1.53), 1.608 (0.59), 1.652 (1.31), 1.685(1.96), 1.734 (0.65), 1.753 (0.65), 1.765 (0.64), 1.932 (0.43), 1.949(0.40), 2.574 (0.66), 2.583 (0.70), 2.602 (0.93), 2.611 (0.85), 2.747(0.93), 2.775 (0.73), 2.914 (0.42), 2.932 (1.05), 2.949 (1.42), 2.966(1.40), 2.976 (1.03), 2.983 (1.09), 3.387 (0.46), 3.647 (0.50), 4.172(0.57), 4.209 (2.03), 4.218 (2.51), 4.426 (0.76), 7.059 (0.99), 7.069(1.04), 7.076 (1.10), 7.086 (1.10), 7.097 (0.41), 7.341 (2.40), 7.352(1.22), 7.361 (2.72), 7.373 (1.08), 7.771 (3.08), 7.775 (2.15), 7.792(2.92), 8.546 (1.52), 8.551 (1.67), 8.557 (1.61), 8.561 (1.51), 8.909(1.01), 8.914 (1.03), 8.926 (1.04), 8.931 (1.11), 8.938 (0.46). LC-MS(method 1): R_(t) = 0.76 min; m/z = 472 (M + H)⁺. 45

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.17-1.29 (m, 6H), 1.36-1.50 (m,0.7H), 1.55-1.92 (m, 4.3H), 1.95-2.10 (m, 1H), 2.62-2.79 (m, 1.4H),2.86-3.00 (m, 1.6H), 3.04-3.16 (m, 1H), 3.35-3.52 (m, 1.4H), 3.90 (br.s, 0.4H), 3.95-4.07 (m, 0.4H), 4.17-4.38 (m, 2H), 4.58 (br. s, 0.6H),7.03-7.22 (m, 2H), 7.24-7.40 (m, 3.2H), 7.41-7.75 (m, 0.8H), 7.78-7.84(m, 2H), 7.88-8.09 (m, 1H), 8.56 (td, 1H), 8.90-9.04 (m, 1H). LC-MS(method 1): R_(t) = 0.79 min; m/z = 547 (M + H)⁺. 46

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.90), 0.008 (0.94), 1.238(15.45), 1.247 (7.17), 1.255 (16.00), 1.264 (6.62), 1.362 (0.49), 1.374(0.55), 1.385 (0.44), 1.396 (0.65), 1.408 (0.61), 1.601 (0.49), 1.613(0.55), 1.662 (1.26), 1.746 (0.50), 1.773 (0.63), 1.783 (0.66), 1.811(1.08), 1.965 (0.51), 1.979 (0.54), 1.995 (0.55), 2.723 (0.65), 2.733(0.72), 2.752 (0.89), 2.761 (0.81), 2.916 (0.51), 2.933 (1.80), 2.942(0.68), 2.951 (1.66), 2.959 (1.37), 2.967 (1.17), 2.977 (0.47), 2.985(0.44), 3.010 (0.92), 3.269 (1.33), 4.199 (1.88), 4.320 (0.46), 4.266(2.60), 4.277 (2.30), 4.612 (1.00), 7.079 (0.63), 7.090 (0.81), 7.096(1.34), 7.106 (1.48), 7.123 (0.82), 7.193 (0.49), 7.216 (0.59), 7.239(0.47), 7.251 (0.52), 7.268 (1.73), 7.287 (2.55), 7.311 (1.40), 7.355(3.35), 7.376 (4.38), 7.399 (1.37), 7.454 (0.44), 7.474 (0.79), 7.490(0.78), 7.777 (1.87), 7.792 (2.10), 7.797 (2.40), 7.809 (1.67), 8.544(0.62), 8.549 (0.71), 8.554 (0.78), 8.559 (2.15), 8.564 (1.83), 8.569(1.69), 8.574 (1.58), 8.925 (0.57), 8.930 (0.59), 8.943 (0.65), 8.947(0.69), 8.961 (0.93), 8.975 (0.90). LC-MS (method 1): R_(t) = 0.77 min;m/z = 498 (M + H)⁺. 47

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.95), 0.008 (1.00), 1.238(15.47), 1.247 (7.15), 1.255 (16.00), 1.264 (6.67), 1.363 (0.47), 1.374(0.53), 1.385 (0.44), 1.397 (0.65), 1.409 (0.62), 1.601 (0.50), 1.614(0.55), 1.662 (1.22), 1.736 (0.49), 1.773 (0.62), 1.784 (0.66), 1.811(1.04), 1.965 (0.50), 1.993 (0.54), 2.724 (0.64), 2.732 (0.73), 2.752(0.87), 2.761 (0.81), 2.916 (0.51), 2.933 (1.77), 2.951 (1.64), 2.959(1.34), 2.967 (1.14), 2.976 (0.47), 2.985 (0.44), 3.008 (0.90), 3.268(1.30), 4.199 (1.84), 4.230 (0.45), 4.267 (2.58), 4.277 (2.27), 4.611(0.97), 7.079 (0.62), 7.090 (0.79), 7.096 (1.32), 7.107 (1.48), 7.123(0.80), 7.194 (0.49), 7.216 (0.60), 7.240 (0.45), 7.252 (0.50), 7.268(1.71), 7.288 (2.54), 7.311 (1.41), 7.356 (3.33), 7.377 (4.34), 7.399(1.36), 7.454 (0.44), 7.475 (0.77), 7.490 (0.77), 7.777 (1.86), 7.792(2.08), 7.797 (2.39), 7.809 (1.66), 8.544 (0.62), 8.549 (0.69), 8.554(0.77), 8.559 (2.20), 8.564 (1.84), 8.569 (1.70), 8.574 (1.58), 8.925(0.57), 8.930 (0.58), 8.943 (0.64), 8.948 (0.68), 8.959 (0.92), 8.975(0.89). LC-MS (method 1): R_(t) = 0.76 min; m/z = 498 (M + H)⁺. 48

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (dd, 6H), 1.39-1.50 (m, 0.6H),1.58-2.10 (m, 5.4H), 2.60-2.84 (m, 1.5H), 2.85-3.00 (m, 1.6H), 3.09 (br.s, 0.6H), 3.18 (br. s, 0.4H), 3.22-3.40 (m, 0.9H), 3.43-3.54 (m, 0.6H),3.57 (s, 1.3H), 3.79 (s, 1.7H), 3.88 (br. s, 0.4H), 4.02-4.15 (m, 0.4H),4.20-4.40 (m, 2H), 4.58 (br. s, 0.6H), 6.72-6.92 (m, 1H), 6.96-7.13 (m,2H), 7.24-7.43 (m, 2H), 7.63-7.86 (m, 3H), 8.55 (td, 1H), 8.98 (dt, 1H).LC-MS (method 1): R_(t) = 0.74 min; m/z = 511 (M + H)⁺. 49

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.15-1.32 (m, 6H), 1.33-1.53 (m,0.6H), 1.57-2.11 (m, 5.4H), 2.58-2.81 (m, 1.4H), 2.86-3.01 (m, 1.6H),3.03-3.21 (m, 1H), 3.24-3.43 (m, 1.2H), 3.58 (s, 1.2H), 3.70 (br. s,0.4H), 3.78 (s, 1.8H), 4.05-4.17 (m, 0.4H), 4.17-4.39 (m, 2H), 4.58 (br.s, 0.6H), 6.80-7.00 (m, 1H), 7.08 (ddd, 1H), 7.27-7.44 (m, 2H),7.63-7.69 (m, 3H), 8.49-8.59 (m, 1H), 8.97 (dt, 1H). LC-MS (method 1):R_(t) = 0.77 min; m/z = 529 (M + H)⁺. 50

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.20), 0.008 (1.19), 1.237(15.36), 1.243 (7.29), 1.254 (16.00), 1.260 (7.11), 1.408 (0.52), 1.419(0.55), 1.431 (0.42), 1.443 (0.61), 1.455 (0.55), 1.646 (0.48), 1.671(0.89), 1.691 (1.13), 1.769 (0.44), 1.780 (0.51), 1.807 (0.99), 1.820(1.01), 1.844 (0.84), 1.988 (0.50), 2.001 (0.50), 2.018 (0.57), 2.524(0.88), 2.582 (0.41), 2.661 (0.59), 2.670 (0.48), 2.718 (0.67), 2.727(0.74), 2.747 (1.00), 2.756 (0.88), 2.868 (1.01), 2.897 (0.74), 2.910(0.49), 2.927 (0.98), 2.944 (1.27), 2.962 (0.94), 3.077 (0.86), 3.147(0.66), 3.160 (1.18), 3.184 (0.59), 3.196 (0.60), 3.207 (0.54), 3.219(0.65), 3.608 (3.83), 3.792 (15.73), 4.239 (1.97), 4.271 (2.12), 4.298(2.12), 4.334 (0.76), 4.572 (1.02), 6.823 (1.23), 6.845 (1.27), 6.900(3.37), 6.922 (3.48), 7.072 (2.09), 7.082 (2.12), 7.089 (2.08), 7.099(2.09), 7.330 (3.38), 7.351 (3.88), 7.356 (1.84), 7.377 (1.40), 7.755(4.00), 7.776 (3.62), 7.785 (2.25), 7.807 (2.51), 7.854 (3.36), 7.877(3.23), 8.538 (0.58), 8.542 (0.63), 8.548 (0.64), 8.556 (1.61), 8.561(1.70), 8.566 (1.61), 8.571 (1.49), 8.941 (1.49), 8.946 (1.57), 8.958(1.62), 8.963 (1.47), 8.972 (0.58). LC-MS (method 1): R_(t) = 0.81 min;m/z = 545/547 (M + H)⁺. 51

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.80), 0.008 (0.84), 1.218(15.11), 1.236 (16.00), 1.242 (9.88), 1.260 (9.22), 1.423 (0.48), 1.435(0.54), 1.446 (0.42), 1.458 (0.61), 1.470 (0.56), 1.625 (0.62), 1.651(0.84), 1.676 (1.00), 1.690 (0.77), 1.703 (0.72), 1.742 (0.48), 1.770(0.52), 1.779 (0.57), 1.795 (0.42), 1.807 (0.52), 1.845 (0.89), 1.866(1.09), 1.980 (0.49), 1.996 (0.59), 2.010 (0.75), 2.524 (0.60), 2.665(0.52), 2.682 (0.65), 2.694 (0.58), 2.731 (1.44), 2.738 (1.09), 2.759(1.30), 2.767 (1.01), 2.907 (0.93), 2.925 (1.94), 2.934 (1.33), 2.942(1.09), 2.952 (1.25), 2.958 (1.16), 2.968 (0.65), 3.067 (0.91), 3.076(0.88), 3.119 (0.52), 3.357 (0.84), 3.369 (0.65), 3.380 (0.77), 3.390(0.77), 3.426 (0.61), 3.440 (0.93), 3.452 (0.50), 3.475 (0.49), 3.902(0.61), 3.991 (0.46), 4.026 (0.41), 4.220 (2.90), 4.236 (0.86), 4.272(2.20), 4.297 (2.24), 4.333 (0.72), 4.577 (1.05), 7.072 (1.55), 7.077(1.10), 7.082 (1.67), 7.088 (2.22), 7.094 (2.24), 7.099 (1.71), 7.104(1.03), 7.113 (1.32), 7.161 (2.10), 7.181 (2.21), 7.252 (0.77), 7.266(1.24), 7.284 (1.31), 7.311 (3.44), 7.331 (3.73), 7.357 (2.31), 7.366(2.23), 7.370 (2.30), 7.375 (2.59), 7.386 (2.22), 7.433 (1.55), 7.552(2.69), 7.615 (0.72), 7.734 (1.26), 7.787 (4.08), 7.800 (2.78), 7.808(3.87), 7.820 (2.15), 7.934 (0.93), 7.954 (1.24), 7.974 (0.84), 8.013(1.64), 8.033 (2.12), 8.052 (1.47), 8.543 (0.89), 8.548 (1.04), 8.553(2.38), 8.558 (2.44), 8.563 (1.63), 8.568 (1.46), 8.962 (1.49), 8.967(1.57), 8.973 (1.08), 8.979 (2.10), 8.984 (1.51), 8.990 (0.95), 8.995(0.81). LC-MS (method 1): R_(t) = 0.79 min; m/z = 547 (M + H)⁺. 52

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (0.63), 0.008 (0.57), 1.243(15.74), 1.261 (16.00), 1.434 (0.72), 1.447 (0.75), 1.457 (0.70), 1.470(0.91), 1.481 (1.03), 1.489 (1.15), 1.509 (1.28), 1.526 (1.57), 1.546(2.00), 1.556 (1.68), 1.566 (1.60), 1.610 (0.62), 1.652 (1.36), 1.685(2.06), 1.701 (1.19), 1.734 (0.69), 1.753 (0.67), 1.765 (0.66), 1.776(0.58), 1.931 (0.45), 1.947 (0.42), 2.523 (0.41), 2.574 (0.70), 2.583(0.73), 2.602 (0.97), 2.611 (0.89), 2.747 (0.97), 2.775 (0.78), 2.914(0.42), 2.932 (1.07), 2.949 (1.46), 2.966 (1.43), 2.976 (1.07), 2.983(1.12), 3.387 (0.49), 3.647 (0.52), 3.684 (0.42), 4.173 (0.58), 4.209(2.11), 4.218 (2.62), 4.426 (0.80), 7.059 (0.98), 7.070 (1.04), 7.076(1.09), 7.087 (1.11), 7.097 (0.41), 7.341 (2.44), 7.353 (1.24), 7.361(2.76), 7.373 (1.09), 7.771 (3.12), 7.776 (2.19), 7.792 (2.96), 8.547(1.46), 8.551 (1.61), 8.557 (1.55), 8.562 (1.45), 8.909 (1.01), 8.914(1.04), 8.926 (1.06), 8.931 (1.13), 8.938 (0.46), 8.951 (0.40). LC-MS(method 1): R_(t) = 0.75 min; m/z = 472 (M + H)⁺. 53

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (dd, 6H), 1.29-1.40 (m, 0.5H),1.41-1.57 (m, 2H), 1.59-1.82 (m, 1.5H), 1.90-2.30 (m, 2H), 2.88-3.01 (m,1.5H), 3.06-3.14 (m, 0.5H), 3.16-3.36 (m, 3.4H, partially covered by H₂Osignal), 3.44 (br. d, 0.6H), 3.78 (d, 3H), 3.93 (br. d, 0.5H), 4.11-4.33(m, 2.5H), 6.92 (dd, 1H), 7.04-7.14 (m, 1H), 7.31-7.41 (m, 2H),7.71-7.84 (m, 3H), 8.52-8.60 (m, 1H), 9.12 (dd, 1H). LC-MS (method 2):R_(t) = 1.80 min; m/z = 529 (M + H)⁺. 54

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.13-1.36 (m, 6.5H), 1.38-1.58 (m,1.5H), 1.58-1.73 (m, 1.5H), 1.78-1.90 (m, 0.5H), 1.90-2.14 (m, 1H),2.14-2.30 (m, 1H), 2.87-3.00 (m, 1.5H), 3.02-3.14 (m, 1.4H), 3.15-3.37(m, 2.5H, partially covered by H₂O signal), 3.44 (br. d, 0.6H), 3.79 (d,3H), 3.94-4.05 (m, 0.5H), 4.12-4.36 (m, 2.5H), 6.90 (dd, 1H), 7.04-7.14(m, 1H), 7.28-7.42 (m, 2H), 7.70- 7.90 (m, 3H), 8.50-8.62 (m, 1H),9.06-9.19 (m, 1H). LC-MS (method 2): R_(t) = 1.88 min; m/z = 545/547(M + H)⁺. 55

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (d, 6H), 1.40-1.57 (m, 2.5H),1.59-1.70 (m, 1H), 1.70-1.81 (m, 0.5H), 1.91-2.12 (m, 1H), 2.12-2.29 (m,1H), 2.87-3.01 (m, 1.5H), 3.10-3.47 (m, 4H, partially covered by H₂Osignal), 3.52 (br. d, 0.5H), 3.75-3.86 (m, 3.5H), 4.12-4.33 (m, 2.5H),6.86 (dd, 1H), 7.03 (dd, 1H), 7.10 (td, 1H), 7.36 (dd, 2H), 7.70-7.85(m, 3H), 8.56 (dt, 1H), 9.07-9.15 (m, 1H). LC-MS (method 2): R_(t) =1.72 min; m/z = 511 (M + H)⁺. 56

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (d, 6H), 1.31-1.56 (m, 2.5H),1.59-1.75 (m, 1.5H), 1.89-2.11 (m, 1H), 2.12-2.29 (m, 1H), 2.88-3.01 (m,1.5H), 3.05-3.39 (m, 3.5H, partially covered by H₂O signal), 3.40-3.51(m, 1H), 3.81 (br. d, 0.5H), 4.14 (br. d, 0.5H), 4.24 (br. d, 2H),7.03-7.19 (m, 2H), 7.30-7.41 (m, 3.25H), 7.54 (d, 0.5H), 7.72 (d,0.25H), 7.79 (dd, 2H), 7.99 (q, 1H), 8.53- 8.62 (m, 1H), 9.10 (ddd, 1H).LC-MS (method 2): R_(t) = 1.83 min; m/z = 547 (M + H)⁺. 57

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.19-1.36 (m, 7.5H), 1.36-1.84 (m,11H), 1.88-2.24 (m, 2H), 2.72 (dd, 0.75H), 2.81-3.02 (m, 2H), 3.07-3.19(m, 0.75H), 3.21-3.36 (m, 2H, partially covered by H₂O signal), 3.52(br. d, 0.4H), 3.57-3.70 (m, 1H), 4.03 (br. d, 0.6H), 4.17-4.30 (m, 2H),7.09 (dd, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 8.57 (dd, 1H), 9.03-9.13 (m,1H). LC-MS (method 2): R_(t) = 1.83 min; m/z = 472 (M + H)⁺. 58

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (dd, 6H), 1.29-1.40 (m, 0.5H),1.41-1.56 (m, 2H), 1.59-1.82 (m, 1.5H), 1.91-2.29 (m, 2H), 2.88-3.01 (m,1.5H), 3.06-3.15 (m, 0.5H), 3.16-3.37 (m, 3.4H, partially covered by H₂Osignal ), 3.44 (br. d, 0.6H), 3.78 (d, 3H), 3.93 (br. d, 0.5H),4.12-4.33 (m, 2.5H), 6.92 (dd, 1H), 7.05-7.14 (m, 1H), 7.32-7.41 (m,2H), 7.71-7.84 (m, 3H), 8.52-8.60 (m, 1H), 9.12 (dd, 1H). LC-MS (method1): R_(t) = 0.92 min; m/z = 529 (M + H)⁺. 59

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.19-1.36 (m, 6.5H), 1.38-1.58 (m,1.5H), 1.58-1.72 (m, 1.5H), 1.78-1.90 (m, 0.5H), 1.91-2.14 (m, 1H),2.14-2.29 (m, 1H), 2.88-3.00 (m, 1.5H), 3.02-3.14 (m, 1.4H), 3.15-3.36(m, 2.5H, partially covered by H₂O signal), 3.44 (br. d, 0.6H), 3.79 (d,3H), 3.94-4.05 (m, 0.5H), 4.13-4.36 (m, 2.5H), 6.90 (dd, 1H), 7.05-7.14(m, 1H), 7.32-7.42 (m, 2H), 7.73- 7.90 (m, 3H), 8.52-8.62 (m, 1H),9.08-9.19 (m, 1H). LC-MS (method 1): R_(t) = 0.96 min; m/z = 545/547(M + H)⁺. 60

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (d, 6H), 1.39-1.57 (m, 2.5H),1.59-1.70 (m, 1H), 1.70-1.81 (m, 0.5H), 1.89-2.12 (m, 1H), 2.12-2.29 (m,1H), 2.87-3.01 (m, 1.5H), 3.10-3.47 (m, 4H, partially covered by H₂Osignal), 3.52 (br. d, 0.5H), 3.75-3.88 (m, 3.5H), 4.12-4.34 (m, 2.5H),6.86 (dd, 1H), 7.03 (dd, 1H), 7.10 (td, 1H), 7.36 (dd, 2H), 7.71-7.84(m, 3H), 8.57 (dt, 1H), 9.06-9.15 (m, 1H). LC-MS (method 1): R_(t) =0.88 min; m/z = 511 (M + H)⁺. 61

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.24 (dd, 6H), 1.31-1.57 (m, 2.5H),1.59-1.75 (m, 1.5H), 1.89-2.11 (m, 1H), 2.12-2.29 (m, 1H), 2.87-3.01 (m,1.5H), 3.04-3.39 (m, 3.5H, partially covered by H₂O signal), 3.39-3.51(m, 1H), 3.81 (br. d, 0.5H), 4.14 (br. d, 0.5H), 4.25 (br. d, 2H),7.05-7.19 (m, 2H), 7.29-7.41 (m, 3.5H), 7.54 (d, 0.5H), 7.72 (d, 0.25H),7.79 (dd, 2H), 7.99 (q, 1H), 8.53- 8.62 (m, 1H), 9.10 (ddd, 1H). LC-MS(method 2): R_(t) = 1.82 min; m/z = 547 (M + H)⁺. 62

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.20-1.36 (m, 7.5H), 1.36-1.83 (m,11H), 1.88-2.24 (m, 2H), 2.72 (dd, 0.75H), 2.81-3.02 (m, 2H), 3.07-3.18(m, 0.75H), 3.21-3.36 (m, 2H, partially covered by H₂O signal), 3.52(br. d, 0.4H), 3.57-3.70 (m, 1H), 4.03 (br. d, 0.6H), 4.16-4.30 (m, 2H),7.09 (dd, 1H), 7.37 (d, 2H), 7.79 (d, 2H), 8.57 (dd, 1H), 9.03-9.13 (m,1H). LC-MS (method 2): R_(t) = 1.82 min; m/z = 472 (M + H)⁺. 63

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.00-1.12 (m, 0.5H), 1.16-1.36 (m,7H), 1.37-1.74 (m, 3.25H), 1.89-2.29 (m, 2H), 2.87-3.39 (m, 5.25H,partially covered by H₂O signal), 3.45 (br. d, 0.5H), 4.07 (br. d,0.5H), 4.23 (br. d, 2H), 7.05-7.16 (m, 1H), 7.16-7.32 (m, 3H), 7.37 (t,2H), 7.41-7.51 (m, 1H), 7.78 (dd, 2H), 8.53-8.61 (m, 1H), 9.04-9.15 (m,1H). LC-MS (method 2): R_(t) = 1.81 min; m/z = 498 (M + H)⁺. [α]_(D) ²⁰= −8.72° (c = 0.260, Methanol). 64

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.00-1.12 (m, 0.5H), 1.17-1.36 (m,7H), 1.38-1.74 (m, 3.25H), 1.89-2.29 (m, 2H), 2.87-3.40 (m, 5.25H,partially covered by H₂O signal), 3.45 (br. d, 0.5H), 4.07 (br. d,0.5H), 4.23 (br. d, 2H), 7.05-7.16 (m, 1H), 7.16-7.32 (m, 3H), 7.37 (t,2H), 7.41-7.51 (m, 1H), 7.78 (dd, 2H), 8.54-8.61 (m, 1H), 9.03-9.15 (m,1H). LC-MS (method 2): R_(t) = 1.82 min; m/z = 498 (M + H)⁺. [α]_(D) ²⁰= +7.98° (c = 0.280, Methanol). 65

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.67), −0.008 (4.28), 0.008(4.04), 0.147 (0.54), 1.401 (1.79), 1.413 (1.82), 1.435 (2.05), 1.446(2.05), 1.651 (5.25), 1.681 (3.33), 1.724 (1.68), 1.762 (1.95), 1.790(1.89), 1.853 (3.67), 1.995 (2.19), 2.328 (1.35), 2.367 (1.25), 2.581(1.45), 2.594 (1.58), 2.610 (2.09), 2.623 (1.85), 2.671 (1.48), 2.710(5.39), 2.718 (3.17), 2.738 (5.09), 2.747 (3.54), 2.865 (3.77), 2.894(2.73), 3.039 (3.23), 3.118 (2.05), 3.330 (3.77), 3.343 (2.80), 3.353(3.60), 3.364 (2.63), 3.411 (3.40), 3.424 (1.92), 3.447 (1.58), 3.819(2.22), 4.033 (1.58), 4.067 (1.45), 4.221 (10.91), 4.238 (2.53), 4.274(8.66), 4.290 (8.56), 4.326 (2.12), 4.569 (3.74), 7.084 (5.22), 7.094(6.84), 7.101 (5.83), 7.107 (4.01), 7.112 (6.80), 7.123 (3.37), 7.288(4.95), 7.309 (5.42), 7.376 (8.35), 7.396 (8.62), 7.465 (4.72), 7.484(6.37), 7.491 (14.18), 7.512 (16.00), 7.527 (8.49), 7.545 (15.43), 7.566(9.30), 7.882 (15.66), 7.904 (14.28), 7.922 (9.87), 7.943 (8.39), 8.050(3.60), 8.070 (5.05), 8.089 (3.13), 8.126 (5.89), 8.146 (8.45), 8.166(5.09), 8.569 (3.40), 8.574 (3.84), 8.580 (8.62), 8.585 (8.89), 8.590(6.27), 8.595 (5.66), 8.982 (5.12), 8.987 (5.25), 8.999 (5.29), 9.004(5.29), 9.010 (3.50), 9.015 (3.27), 9.028 (3.03), 9.032 (3.03). LC-MS(method 1): R_(t) = 0.81 min; m/z = 557/559 (M + H)⁺. 66

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36-1.50 (m, 0.6H), 1.55-2.06 (m,5.4H), 2.57-2.93 (m, 2H), 2.99-3.18 (m, 1H), 3.35-3.49 (m, 1.6H),3.77-3.86 (m, 0.4H), 4.01-4.11 (m, 0.4H), 4.20-4.36 (m, 2H), 4.52-4.61(m, 0.6H), 7.10 (dt, 1H), 7.24-7.43 (m, 1H), 7.44-7.62 (m, 3H),7.84-8.00 (m, 2H), 8.02-8.19 (m, 1H), 8.51-8.64 (m, 1H), 8.91-9.10 (m,1H). LC-MS (method 2): R_(t) = 1.57 min; m/z = 557/559 (M + H)⁺. 67

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.150 (0.63), 0.008 (3.74), 1.423(1.51), 1.447 (1.69), 1.622 (2.57), 1.637 (3.51), 1.673 (2.97), 1.760(1.71), 1.852 (2.80), 1.989 (2.37), 2.073 (2.66), 2.327 (1.23), 2.366(1.00), 2.650 (1.03), 2.679 (2.34), 2.690 (1.80), 2.722 (4.06), 2.750(3.69), 2.887 (2.97), 2.917 (2.17), 3.021 (2.63), 3.107 (1.63), 3.351(2.49), 3.373 (2.23), 3.424 (2.89), 3.461 (1.31), 3.893 (1.91), 3.985(1.31), 4.022 (1.34), 4.221 (8.97), 4.241 (1.51), 4.278 (7.77), 4.286(7.74), 4.323 (1.09), 4.559 (3.03), 7.094 (4.77), 7.097 (5.06), 7.108(5.20), 7.114 (9.40), 7.125 (4.69), 7.160 (6.40), 7.180 (6.71), 7.232(2.20), 7.293 (3.86), 7.311 (4.11), 7.338 (6.34), 7.356 (6.54), 7.406(3.89), 7.414 (4.66), 7.508 (11.46), 7.529 (12.60), 7.550 (7.23), 7.571(7.77), 7.588 (7.89), 7.596 (2.40), 7.769 (3.63), 7.900 (12.77), 7.922(16.00), 7.940 (5.40), 7.944 (7.00), 7.960 (3.94), 7.980 (2.49), 8.010(4.74), 8.030 (6.14), 8.050 (4.14), 8.571 (2.71), 8.575 (3.51), 8.581(7.37), 8.586 (7.54), 8.591 (4.91), 8.596 (4.31), 8.988 (4.20), 8.993(4.11), 9.005 (4.37), 9.010 (4.60), 9.018 (2.77), 9.031 (2.51). LC-MS(method 1): R_(t) = 0.76 min; m/z = 539/541 (M + H)⁺. 68

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.149 (0.59), −0.008 (4.53), 0.008(4.08), 0.146 (0.52), 1.412 (1.34), 1.423 (1.45), 1.435 (1.23), 1.446(1.71), 1.459 (1.60), 1.623 (2.56), 1.648 (3.53), 1.673 (3.04), 1.759(1.60), 1.853 (2.82), 1.990 (1.82), 2.073 (3.19), 2.328 (1.11), 2.366(1.30), 2.524 (3.53), 2.650 (0.89), 2.678 (2.26), 2.691 (1.86), 2.711(1.82), 2.722 (4.08), 2.750 (3.64), 2.760 (3.04), 2.888 (3.08), 2.916(2.19), 3.031 (2.52), 3.104 (1.52), 3.350 (2.38), 3.373 (2.26), 3.425(2.78), 3.438 (1.60), 3.461 (1.30), 3.892 (1.78), 3.986 (1.41), 4.021(1.26), 4.221 (8.98), 4.241 (1.34), 4.278 (7.76), 4.286 (7.83), 4.322(1.08), 4.558 (3.04), 7.097 (5.53), 7.101 (3.56), 7.107 (5.16), 7.114(9.50), 7.124 (4.90), 7.128 (3.23), 7.160 (6.50), 7.181 (6.79), 7.232(2.34), 7.293 (3.97), 7.312 (4.08), 7.338 (6.46), 7.357 (6.61), 7.406(4.12), 7.414 (4.94), 7.508 (11.62), 7.529 (13.10), 7.550 (7.20), 7.571(8.13), 7.588 (8.32), 7.596 (2.41), 7.769 (3.71), 7.900 (13.07), 7.922(16.00), 7.940 (5.46), 7.945 (7.31), 7.960 (3.94), 7.980 (2.60), 8.010(4.86), 8.030 (6.27), 8.049 (4.34), 8.570 (2.82), 8.575 (3.42), 8.581(7.42), 8.586 (7.61), 8.591 (4.94), 8.596 (4.45), 8.988 (4.23), 8.993(4.34), 9.005 (4.38), 9.010 (4.60), 9.018 (2.67), 9.030 (2.60), 9.035(2.30). LC-MS (method 1): R_(t) = 0.75 min; m/z = 539/541 (M + H)⁺.

Analogously to Examples 13-16, the following compounds were preparedfrom the starting materials specified in each case:

Name/Structure/Starting materials Example Analytical data 69[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2- fluorophenyl)methanone(racemtate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl (2-fluorophenyl)methanone (racemate)¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.21- 1.35 (m, 0.5H), 1.35-1.47 (m,1.5H), 1.51-1.67 (m, 1H), 1.68-1.79 (m, 0.5H), 1.79-1.93 (m, 1H),1.93-2.20 (m, 2H), 2.30-2.45 (m, 1.5H), 2.55-2.68 (m, 1H), 2.70-2.85 (m,1H), 3.62-3.81 (m, 1H), 3.99-4.24 (m, 2H), 4.43- 4.64 (m, 1H), 6.91-7.03(m, 1H), 7.18-7.28 (m, 2H), 7.28-7.37 (m, 2H), 7.42-7.48 (m, 1H), 7.53(dd, 2H), 7.60 (dd, 1H), 7.93 (dd, 2H), 8.60 (dd, 1H). LC-MS (method 2):R_(t) = 1.60 min; m/z = 489/491 (M + H)⁺. 70[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl) methanone(racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl (6-methoxypyridin-2-yl)methanone(racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (2.46), 0.008(2.02), 1.328 (0.55), 1.365 (0.56), 1.393 (0.56), 1.478 (0.46), 1.633(1.82), 1.654 (0.70), 1.746 (0.52), 1.776 (0.43), 1.806 (0.48), 1.828(0.83), 1.856 (1.18), 1.875 (1.04), 1.893 (0.57), 1.989 (0.96), 2.009(0.83), 2.058 (0.53), 2.092 (0.46), 2.328 (0.66), 2.367 (0.96), 2.390(0.67), 2.423 (0.72), 2.459 (1.06), 2.524 (1.29), 2.568 (1.07), 2.598(0.92), 2.621 (0.65), 2.664 (1.20), 2.686 (0.68), 2.710 (0.51), 2.738(0.62), 2.771 (0.52), 2.826 (0.47), 2.849 (0.41), 3.755 (14.92), 3.791(16.00), 4.095 (4.59), 4.134 (2.13), 4.154 (2.17), 4.190 (0.61), 4.430(0.57), 4.451 (1.12), 4.471 (0.60), 4.583 (0.45), 4.611 (1.18), 4.640(1.06), 4.667 (0.81), 6.890 (3.80), 6.910 (3.98), 6.942 (0.82), 6.957(2.25), 6.959 (2.26), 6.974 (2.33), 6.991 (0.82), 7.228 (2.00), 7.245(2.10), 7.286 (2.22), 7.290 (1.87), 7.305 (2.73), 7.312 (2.17), 7.329(1.71), 7.506 (3.92), 7.513 (4.20), 7.527 (4.44), 7.535 (4.43), 7.585(2.00), 7.588 (2.02), 7.591 (2.02), 7.608 (1.71), 7.611 (1.73), 7.614(1.73), 7.765 (1.61), 7.778 (1.79), 7.783 (1.86), 7.786 (1.91), 7.796(1.95), 7.798 (2.00), 7.804 (1.50), 7.817 (1.48), 7.912 (3.91), 7.934(3.50), 7.952 (4.15), 7.973 (3.67), 8.587 (1.44), 8.608 (2.15), 8.626(1.46). LC-MS (method 2): R_(t) = 1.60 min; m/z = 502/504 (M + H)⁺. 71(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](2-fluorophenyl) methanone(racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and(2-fluorophenyl)[8-oxa-3,10- diazabicyclo[4.3.1]dec-10-yl]methanonetrifluoroacetic acid salt (racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]= 1.488 (2.65), 1.661 (1.13), 2.028 (0.96), 2.440 (1.00), 2.456 (1.59),2.473 (2.09), 2.524 (3.57), 2.671 (0.68), 2.711 (0.81), 2.767 (2.29),2.780 (1.79), 2.802 (2.15), 2.815 (3.34), 2.848(3.60), 3.039 (1.18),3.387 (2.69), 3.416 (2.28), 3.448 (5.59), 3.472 (5.42), 3.538 (2.11),3.546 (2.32), 3.567 (4.55), 3.576 (5.40), 3.604 (6.93), 3.632 (3.21),3.784 (5.22), 3.813 (4.14), 4.125 (1.55), 4.131 (1.57), 4.161 (8.90),4.170 (11.10), 4.188 (4.21), 4.207 (1.61), 4.225 (1.14), 4.466 (2.02),4.484 (2.03), 4.515 (3.24), 4.908 (0.64), 6.854 (0.54), 6.934 (2.39),6.951 (5.95), 6.968 (5.63), 6.984 (2.15), 7.187 (1.02), 7.210 (1.94),7.240 (5.01), 7.262 (5.03), 7.285 (5.16), 7.305 (5.49), 7.324 (6.57),7.341 (4.97), 7.371 (1.56), 7.448 (1.16), 7.462 (2.18), 7.470 (2.52),7.491 (9.03), 7.514 (16.00), 7.536 (10.46), 7.565 (0.67), 7.595 (5.16),7.617 (4.66), 7.629 (3.69), 7.652 (2.95), 7.861 (0.58), 7.882 (0.51),7.944 (5.98), 7.965 (7.09), 7.972 (12.53), 7.993 (10.26), 8.638 (2.48),8.656 (2.46), 8.733 (3.86), 8.750 (3.82). LC-MS (method 2): R_(t) = 1.48min; m/z = 505/507 (M + H)⁺. 72[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](6-methoxypyridin-2-yl)methanone (racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and(6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone bis(trifluoroacetic acid) salt(racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.567 (0.87), 1.592(0.80), 1.788 (0.52), 2.608 (1.26), 2.638 (1.30), 2.657 (0.64), 2.834(1.95), 2.858 (2.13), 2.884 (0.69), 2.966 (0.86), 2.980 (0.97), 2.996(0.69), 3.011 (0.60), 3.430 (1.06), 3.437 (1.03), 3.459 (1.38), 3.466(1.31), 3.484 (0.59), 3.492 (0.60), 3.513 (0.82), 3.521 (0.77), 3.551(1.85), 3.579 (1.68), 3.598 (1.83), 3.604 (1.80), 3.625 (1.64), 3.741(16.00), 3.755 (10.52), 3.768 (2.31), 3.798 (1.62), 3.826 (0.99), 3.844(1.13), 4.030 (0.59), 4.144 (0.83), 4.162 (1.98), 4.171 (2.27), 4.179(2.74), 4.201 (2.58), 4.237 (0.72), 4.420 (0.60), 4.514 (1.25), 6.831(1.53), 6.852 (1.73), 6.865 (3.41), 6.880 (3.01), 6.887 (3.01), 6.895(1.71), 6.912 (1.93), 6.929 (1.02), 7.089 (2.50), 7.106 (2.60), 7.271(0.69), 7.283 (1.18), 7.297 (1.37), 7.305 (1.44), 7.321 (1.10), 7.469(2.60), 7.484 (4.84), 7.489 (3.91), 7.505 (4.37), 7.584 (3.37), 7.606(3.06), 7.620 (1.39), 7.640 (0.89), 7.773 (1.60), 7.792 (2.16), 7.812(1.47), 7.911 (2.78), 7.932 (2.50), 7.959 (4.47), 7.980 (4.02), 8.728(2.05), 8.745 (1.91). LC-MS (method 2): R_(t) = 1.44 min; m/z = 518 (M +H)⁺. 73 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](4-methyl-1,2,5-oxadiazol-3-yl)methanone (racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and(4-methyl-1,2,5-oxadiazol-3-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone trifluoroacetic acidsalt (racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.008 (0.45), 1.596(0.63), 1.631 (0.49), 1.658 (0.43), 1.867 (0.57), 1.888 (0.61), 2.397(14.19), 2.407 (16.00), 2.616 (0.46), 2.638 (0.42), 2.661 (1.05), 2.666(0.98), 2.690 (0.81), 2.697 (0.78), 2.815 (0.74), 2.846 (1.68), 2.879(1.06), 2.897 (0.53), 2.905 (0.65), 2.961 (0.75), 2.977 (0.84), 2.992(0.60), 3.008 (0.54), 3.124 (0.58), 3.146 (0.76), 3.153 (0.68), 3.175(0.60), 3.502 (1.34), 3.530 (1.75), 3.603 (1.20), 3.634 (2.86), 3.661(1.94), 3.688 (0.96), 3.789 (1.53), 3.818 (1.34), 3.826 (1.51), 3.856(1.09), 3.874 (0.83), 3.896 (0.80), 4.006 (0.71), 4.027 (0.66), 4.143(0.55), 4.174 (5.38), 4.194 (2.21), 4.230 (0.50), 4.460 (0.74), 4.540(0.97), 6.709 (0.73), 6.726 (1.45), 6.743 (0.79), 6.819 (0.81), 6.836(1.65), 6.853 (0.90), 7.197 (0.76), 7.219 (0.96), 7.236 (0.83), 7.268(0.86), 7.290 (1.09), 7.307 (0.95), 7.451 (3.37), 7.467 (5.00), 7.472(4.76), 7.488 (4.09), 7.544 (1.78), 7.566 (1.57), 7.578 (1.88), 7.601(1.61), 7.908 (3.71), 7.929 (3.34), 7.946 (4.19), 7.967 (3.71), 8.545(1.42), 8.562 (1.36), 8.666 (1.59), 8.683 (1.53). LC-MS (method 1):R_(t) = 0.80 min; m/z = 493/495 (M + H)⁺. 74[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](2-fluorophenyl)methanone (racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and(2-fluorophenyl)[8-oxa-3,10- diazabicyclo[4.3.1]dec-10-yl]methanonetrifluoroacetic acid salt (racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]= 1.500 (2.79), 1.621 (0.96), 2.019 (0.78), 2.074 (0.43), 2.440 (1.66),2.462 (2.53), 2.479 (2.61), 2.594 (1.63), 2.623 (1.35), 2.670 (0.79),2.711 (0.53), 2.757 (2.07), 2.770 (1.35), 2.792 (1.80), 2.825 (2.83),2.852 (3.46), 2.972 (1.24), 3.387 (1.98), 3.441 (3.65), 3.467 (5.66),3.524 (1.84), 3.533 (1.91), 3.562 (3.97), 3.569 (4.03), 3.589 (3.16),3.607 (4.51), 3.637 (2.37), 3.762 (1.88), 3.778 (3.80), 3.808 (2.72),4.157 (1.54), 4.193 (9.08), 4.203 (10.44), 4.239 (1.92), 4.482 (4.20),6.950 (0.61), 7.082 (2.69), 7.098 (4.45), 7.109 (4.38), 7.124 (1.90),7.207 (1.12), 7.231 (2.74), 7.251 (5.42), 7.264 (5.91), 7.286 (5.03),7.309 (3.28), 7.403 (1.40), 7.417 (1.47), 7.452 (1.51), 7.466 (2.25),7.473 (2.88), 7.486 (2.71), 7.495 (1.60), 7.509 (1.08), 7.523 (6.63),7.544 (16.00), 7.566 (9.86), 7.601 (0.43), 7.948 (4.54), 7.970 (5.54),7.976 (10.99), 7.998 (8.96), 8.590 (6.44), 8.595 (6.11), 8.600 (6.16),9.116 (2.08), 9.131 (2.05), 9.172 (3.27), 9.176 (3.32), 9.190 (3.27).LC-MS (method 2): R_(t) = 1.69 min; m/z = 506/508 (M +H)⁺. 75[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](6-methoxypyridin-2-yl)methanone (racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and(6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone bis(trifluoroacetic acid)salt (racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.570 (0.60), 1.593(0.57), 1.645 (0.41), 1.825 (0.43), 2.628 (0.86), 2.660 (0.80), 2.805(1.01), 2.824 (1.36), 2.855 (1.36), 2.919 (0.72), 2.932 (0.88), 2.948(0.49), 2.964 (0.45), 3.287 (1.05), 3.357 (0.74), 3.371 (0.52), 3.429(0.89), 3.451 (1.04), 3.457 (1.04), 3.491 (0.52), 3.499 (0.56), 3.520(0.69), 3.529 (0.67), 3.546 (1.40), 3.576 (1.47), 3.596 (1.73), 3.612(1.16), 3.624 (1.37), 3.746 (16.00), 3.762 (2.17), 3.791 (1.61), 3.814(1.06), 3.842 (2.71), 3.870 (0.43), 4.056 (0.41), 4.189 (1.31), 4.197(1.28), 4.218 (1.73), 4.236 (1.80), 4.272 (0.46), 4.422 (0.49), 4.488(0.94), 6.848 (0.97), 6.869 (2.62), 6.890 (1.83), 6.951 (0.96), 6.969(1.00), 7.010 (0.63), 7.020 (0.69), 7.027 (0.69), 7.037 (0.72), 7.045(1.05), 7.055 (1.10), 7.062 (1.09), 7.072 (1.06), 7.087 (1.75), 7.105(1.81), 7.503 (1.66), 7.515 (2.91), 7.523 (2.10), 7.536 (3.02), 7.558(0.49), 7.590 (0.44), 7.655 (0.68), 7.674 (0.88), 7.694 (0.59), 7.777(1.12), 7.797 (1.58), 7.816 (1.10), 7.915 (1.73), 7.936 (1.54), 7.963(2.90), 7.984 (2.61), 8.553 (0.73), 8.558 (0.81), 8.569 (1.60), 8.574(1.32), 8.580 (1.22), 8.584 (1.10), 9.172 (1.05), 9.176 (1.19), 9.188(1.22), 9.194 (1.15). LC-MS (method 2): R_(t) = 1.61 min; m/z = 519/521(M +H)⁺. 76 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](4-methyl-1,2,5-oxadiazol-3-yl)methanone (racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and(4-methyl-1,2,5-oxadiazol-3-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone trifluoroacetic acidsalt (racemate) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.607 (0.86), 1.622(0.95), 1.658 (0.51), 1.909 (0.93), 1.924 (0.91), 2.389 (14.10), 2.407(16.00), 2.479 (0.60), 2.525 (0.91), 2.639 (1.35), 2.662 (1.45), 2.669(1.53), 2.814 (0.78), 2.845 (1.77), 2.873 (1.03), 2.900 (1.15), 2.910(1.31), 2.926 (1.43), 2.941 (0.71), 2.957 (0.58), 3.046 (0.67), 3.067(0.86), 3.075 (0.77), 3.097 (0.62), 3.475 (0.83), 3.482 (0.97), 3.491(0.99), 3.503 (1.40), 3.512 (1.24), 3.520 (1.40), 3.527 (1.26), 3.586(0.91), 3.595 (1.55), 3.626 (3.60), 3.637 (2.10), 3.655 (1.38), 3.668(1.21), 3.782 (1.80), 3.812 (1.40), 3.829 (1.64), 3.859 (1.91), 3.886(0.98), 3.940 (0.86), 3.962 (0.82), 4.185 (0.63), 4.209 (6.10), 4.220(2.95), 4.234 (2.63), 4.270 (0.55), 4.470 (0.91), 4.511 (1.21), 6.875(1.29), 6.885 (1.37), 6.892 (1.33), 6.902 (1.31), 6.978 (1.43), 6.988(1.52), 6.995 (1.47), 7.005 (1.45), 7.490 (3.56), 7.502 (4.28), 7.511(4.08), 7.523 (4.26), 7.924 (4.03), 7.946 (4.01), 7.954 (4.78), 7.975(3.99), 8.477 (1.41), 8.482 (1.51), 8.487 (1.51), 8.492 (1.39), 8.561(1.58), 8.565 (1.68), 8.571 (1.66), 8.575 (1.46), 8.948 (1.40), 8.953(1.38), 8.965 (1.42), 8.970 (1.30), 9.103 (1.56), 9.108 (1.54), 9.120(1.58), 9.125 (1.43). LC-MS (method 2): R_(t) = 1.73 min; m/z = 494/496(M +H)⁺. 77 (4-amino-1,2,5-oxadiazo1-3-yl)[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (racemate)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and(4-amino-1,2,5-oxadiazol-3-yl) [8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone bis(trifluoroacetic acid) salt (racemate) ¹H-NMR (500 MHz,DMSO-d₆): δ [ppm] = 1.234 (1.70), 1.567 (1.12), 1.596 (1.63), 1.623(1.40), 1.834 (1.28), 1.892 (1.22), 2.075 (1.63), 2.365 (0.43), 2.607(1.25), 2.635 (1.73), 2.664 (1.94), 2.688 (1.96), 2.782 (1.95), 2.807(2.40), 2.829 (1.46), 2.848 (2.34), 2.869 (2.53), 2.891 (1.06), 2.957(1.60), 2.970 (1.86), 2.981 (1.60), 2.993 (1.52), 3.052 (1.37), 3.069(1.87), 3.092 (1.25), 3.377 (2.05), 3.525 (2.11), 3.543 (3.97), 3.561(2.67), 3.620 (2.85), 3.633 (3.17), 3.644 (3.61), 3.669 (3.93), 3.680(3.80), 3.691 (3.10), 3.704 (2.75), 3.777 (3.33), 3.801 (2.62), 3.821(3.15), 3.844 (2.43), 4.108 (2.18), 4.124 (2.09), 4.161 (0.99), 4.193(16.00), 4.224 (2.81), 4.451 (2.06), 4.494 (2.45), 6.348 (7.64), 6.390(7.95), 6.888 (2.17), 6.897 (2.48), 6.902 (2.55), 6.910 (2.28), 6.969(2.37), 6.977 (2.68), 6.982 (2.78), 6.990 (2.49), 7.455 (0.57), 7.486(6.37), 7.504 (11.79), 7.521 (7.81), 7.571 (0.59), 7.584 (0.57), 7.601(0.49), 7.830 (0.66), 7.847 (0.50), 7.909 (6.89), 7.926 (7.00), 7.936(8.05), 7.953 (7.00), 8.002 (0.44), 8.493 (3.05), 8.498 (3.03), 8.501(2.86), 8.564 (3.37), 8.568 (3.40), 8.572 (3.22), 8.899 (2.70), 8.913(2.68), 9.066 (3.05), 9.076 (2.91), 9.079 (2.96). LC-MS (method 2):R_(t) = 1.57 min; m/z = 495/497 (M + H)⁺. 78[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1) ¹H-NMR (500MHz, DMSO-d₆): δ [ppm] = 1.28- 1.40 (m, 1H), 1.43-1.52 (m, 0.5H),1.53-1.91 (m, 3H), 1.92-2.05 (m, 1H), 2.08-2.19 (m, 0.5H), 2.31-2.45 (m,1.5H), 2.46-2.53 (m, 0.5H, partially covered by DMSO signal), 2.53-2.65(m, 1H), 2.76-2.89 (m, 1H), 3.78 (m, 3H), 3.82-3.94 (m, 1H), 4.07-4.24(m, 2H), 4.49- 4.61 (m, 1H), 6.94 (dt, 1H), 6.98 (td, 1H), 7.32 (ddt,1H), 7.49-7.56 (m, 2H), 7.56-7.63 (m, 1H), 7.72-7.81 (m, 1H), 7.85-8.02(m, 2H), 8.58-8.66 (m, 1H). LC-MS (method 2): R_(t) = 1.59 min; m/z =520/522 (M + H)⁺. 79 [3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2) ¹H-NMR (500MHz, DMSO-d₆): δ [ppm] = 1.29- 1.40 (m, 1H), 1.43-1.52 (m, 0.5H),1.53-1.91 (m, 3H), 1.91-2.06 (m, 1H), 2.08-2.17 (m, 0.5H), 2.33- 2.45(m, 1.5H), 2.47-2.53 (m, 0.5H, partially covered by DMSO signal),2.53-2.65 (m, 1H), 2.75-2.89 (m, 1H), 3.78 (m, 3H), 3.83-3.93 (m, 1H),4.07-4.22 (m, 2H), 4.50-4.61 (m, 1H), 6.94 (dt, 1H), 6.98 (td, 1H), 7.32(ddt, 1H), 7.48-7.56 (m, 2H), 7.57-7.62 (m, 1H), 7.71-7.81 (m, 1H),7.84-8.10 (m, 2H), 8.45- 8.72 (m, 1H). LC-MS (method 2): R_(t) = 1.59min; m/z = 520/522 (M +H)⁺. 80(+)−[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl+methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2- fluorophenyl)methanone(enantiomer 1)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl (2-fluorophenyl)methanone (enantiomer 1)¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] = 1.21- 1.35 (m, 0.5H), 1.35-1.50 (m,1.5H), 1.51-1.65 (m, 1H), 1.65-1.76 (m, 0.5H), 1.78-1.93 (m, 1H),1.94-2.20 (m, 2H), 2.31-2.46 (m, 1.5H), 2.55-2.69 (m, 1H, partiallycovered by DMSO signal), 2.70- 2.83 (m, 1H), 3.66-3.79 (m, 1H),4.04-4.24 (m, 2H), 4.47-4.62 (m, 1H), 7.11-7.18 (m, 1H), 7.19-7.39 (m,3H), 7.42-7.51 (m, 1H), 7.52-7.61 (m, 2H), 7.89- 8.04 (m, 2H), 8.56-8.63(m, 1H), 8.98-9.09 (m, 1H). LC-MS (method 2): R_(t) = 1.77 min; m/z =490/492 (M + H)⁺. [α]_(D) ²⁰ = +18.1° (c = 0.35, Methanol). 81(−)-[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2- fluorophenyl)methanone(enantiomer 2)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl (2-fluorophenyl)methanone (enantiomer 2)¹H-NMR (500 MHz, DMSO-d₆): δ [ppm] = 1.24- 1.36 (m, 0.5H), 1.36-1.48 (m,1.5H), 1.50-1.65 (m, 1H), 1.65-1.76 (m, 0.5H), 1.77-1.92 (m, 1H), 1.93-2.20 (m, 2H), 2.31-2.46 (m, 1.5H), 2.55-2.69 (m, 1H, partially coveredby DMSO signal), 2.70-2.83 (m, 1H), 3.65-3.78 (m, 1H), 4.04-4.24 (m,2H), 4.47- 4.62 (m, 1H), 7.11-7.18 (m, 1H), 7.19-7.39 (m, 3H), 7.41-7.51(m, 1H), 7.52-7.61 (m, 2H), 7.90-8.04 (m, 2H), 8.55-8.63 (m, 1H),8.97-9.08 (m, 1H). LC-MS (method 2): R_(t) = 1.77 min; m/z = 490/492(M + H)⁺. [α]_(D) ²⁰ = −17.69° (c = 0.26, Methanol). 82[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 1) ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = −0.008 (1.33), 0.008 (1.51), 1.323 (0.51),1.351 (1.00), 1.375 (0.65), 1.481 (0.40), 1.597 (1.68), 1.620 (0.66),1.714 (0.70), 1.805 (0.44), 1.864 (0.57), 1.887 (0.76), 1.988 (0.67),2.143 (0.41), 2.328 (0.76), 2.350 (0.98), 2.407 (1.09), 2.437 (0.49),2.569 (1.19), 2.614 (1.24), 2.637 (0.56), 2.670 (0.40), 2.762 (0.64),2.796 (0.81), 3.761 (16.00), 3.788 (12.13), 3.842 (0.60), 3.862 (1.14),3.882 (0.67), 3.904 (0.66), 3.923 (0.67), 4.116 (3.08), 4.133 (0.87),4.168 (2.04), 4.196 (2.11), 4.231 (0.77), 4.540 (0.67), 4.562 (1.14),4.581 (0.77), 6.923 (1.52), 6.931 (1.89), 6.936 (1.30), 6.946 (1.75),6.954 (1.91), 6.958 (1.27), 7.124 (1.78), 7.134 (1.89), 7.141 (1.98),7.151 (1.84), 7.541 (3.17), 7.557 (4.99), 7.562 (4.59), 7.578 (4.61),7.743 (1.54), 7.754 (1.20), 7.765 (2.47), 7.776 (1.94), 7.787 (1.47),7.798 (1.10), 7.921 (3.28), 7.943 (2.94), 7.998 (4.43), 8.019 (3.95),8.594 (2.40), 8.599 (2.44), 9.040 (1.10), 9.045 (1.12), 9.060 (2.05),9.077 (1.40), 9.082 (1.37). LC-MS (method 2): R_(t) = 1.76 min; m/z =521/523 (M + H)⁺. 83[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (enantiomer 2) ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = −0.008 (1.78), 1.325 (0.60), 1.351 (1.03), 1.482(0.41), 1.597 (1.78), 1.624 (0.69), 1.693 (0.75), 1.784 (0.40), 1.803(0.49), 1.835 (0.44), 1.864 (0.60), 1.887 (0.80), 1.987 (0.71), 2.328(0.88), 2.350 (1.02), 2.407 (1.18), 2.435 (0.54), 2.569 (1.28), 2.613(1.33), 2.637 (0.62), 2.670 (0.46), 2.764 (0.65), 2.798 (0.87), 3.761(16.00), 3.788 (12.13), 3.840 (0.66), 3.862 (1.20), 3.881 (0.69), 3.903(0.71), 3.922 (0.70), 4.115 (3.28), 4.132 (0.89), 4.168 (2.16), 4.196(2.26), 4.232 (0.79), 4.540 (0.71), 4.562 (1.22), 4.582 (0.86), 6.923(1.53), 6.931 (1.89), 6.935 (1.31), 6.945 (1.74), 6.953 (1.94), 6.958(1.38), 7.124 (1.83), 7.134 (1.93), 7.141 (2.04), 7.151 (1.88), 7.541(3.16), 7.556 (5.03), 7.562 (4.70), 7.578 (4.61), 7.743 (1.53), 7.754(1.17), 7.765 (2.58), 7.776 (2.00), 7.787 (1.54), 7.798 (1.08), 7.921(3.42), 7.943 (3.01), 7.998 (4.52), 8.019 (4.03), 8.593 (2.48), 8.599(2.52), 9.040 (1.05), 9.045 (1.12), 9.060 (2.18), 9.077 (1.45), 9.082(1.42). LC-MS (method 2): R_(t) = 1.77 min; m/z = 521/523 (M + H)⁺. 84[3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone (enantiomer 1)

from 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone(enantiomer 1) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.008 (1.08), 1.234(0.44), 1.272 (0.56), 1.296 (0.47), 1.338 (0.72), 1.369 (0.41), 1.455(0.49), 1.618 (1.49), 1.643 (0.64), 1.759 (0.89), 1.776 (1.43), 1.798(1.23), 1.826 (1.18), 1.852 (0.79), 1.979 (1.03), 1.999 (0.87), 2.045(0.74), 2.074 (2.25), 2.367 (0.82), 2.379 (0.83), 2.413 (0.91), 2.576(1.39), 2.609 (1.34), 2.653 (2.98), 2.711(0.41), 2.827 (0.71), 2.861(0.55), 2.949 (0.55), 2.971 (0.46), 3.751 (16.00), 3.780 (15.67), 4.421(1.64), 4.437 (1.22), 4.455 (2.27), 4.503 (1.21), 4.537 (1.75), 4.565(1.37), 4.586 (2.44), 4.607 (1.32), 4.634 (1.76), 4.661 (2.00), 4.667(1.62), 4.694 (1.23), 6.882 (3.25), 6.903 (3.37), 6.955 (0.80), 6.970(1.63), 6.988 (1.68), 7.005 (1.72), 7.020 (0.93), 7.225 (2.06), 7.243(2.21), 7.254 (2.17), 7.271 (2.27), 7.320 (0.91), 7.329 (1.02), 7.343(1.88), 7.357 (1.06), 7.366 (1.00), 7.604 (3.20), 7.627 (2.70), 7.765(1.68), 7.773 (1.69), 7.785 (2.17), 7.791 (2.06), 7.804 (1.55), 7.812(1.46), 7.978 (1.43), 7.985 (2.22), 7.992 (1.50), 7.999 (1.81), 8.006(2.76), 8.013 (1.72), 8.188 (2.55), 8.206 (3.33), 8.226 (2.09), 8.560(2.92), 8.577 (2.85), 8.623 (2.28), 8.628 (2.25), 8.666 (2.15), 8.671(2.13). LC-MS (method 2): R_(t) = 1.19 min; m/z = 503/505 (M + H)⁺. 85[3-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone (enantiomer 2)

from 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone(enantiomer 2) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.008 (1.29), 0.008(1.29), 1.234 (0.44), 1.271 (0.51), 1.296 (0.47), 1.340 (0.66), 1.469(0.48), 1.617 (1.38), 1.646 (0.61), 1.760 (0.86), 1.776 (1.32), 1.796(1.13), 1.826 (1.07), 1.852 (0.75), 1.978 (0.92), 1.999 (0.82), 2.045(0.66), 2.074 (0.86), 2.367 (0.78), 2.413 (0.82), 2.577 (1.27), 2.609(1.18), 2.659 (2.73), 2.711 (0.45), 2.827 (0.63), 2.862 (0.51), 2.951(0.48), 2.972 (0.42), 3.751 (16.00), 3.780 (15.74), 4.421 (1.55), 4.437(1.13), 4.455 (2.11), 4.503 (1.14), 4.537 (1.64), 4.566 (1.26), 4.586(2.25), 4.607 (1.19), 4.633 (1.65), 4.660 (1.86), 4.667 (1.53), 4.695(1.18), 6.882 (3.15), 6.903 (3.25), 6.955 (0.77), 6.972 (1.54), 6.989(1.58), 7.005 (1.63), 7.023 (0.87), 7.225 (2.02), 7.243 (2.09), 7.254(2.11), 7.271 (2.13), 7.320 (0.91), 7.329 (0.97), 7.343 (1.79), 7.357(0.99), 7.365 (0.94), 7.606 (3.07), 7.629 (2.56), 7.765 (1.72), 7.772(1.70), 7.785 (2.11), 7.793 (1.98), 7.804 (1.58), 7.812 (1.48), 7.977(1.52), 7.985 (2.27), 7.992 (1.58), 7.999 (1.89), 8.006 (2.77), 8.013(1.75), 8.188 (2.52), 8.206 (3.16), 8.227 (1.99), 8.560 (2.73), 8.578(2.64), 8.623 (2.34), 8.628 (2.31), 8.666 (2.22), 8.671 (2.22). LC-MS(method 2): R_(t) = 1.17 min; m/z = 503/505 (M + H)⁺. 86[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone (enantiomer 1)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone(enantiomer 1) ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.234 (0.72), 1.336(0.56), 1.363 (0.61), 1.393 (0.57), 1.500 (0.49), 1.620 (1.56), 1.638(0.78), 1.669 (0.48), 1.715 (0.50), 1.863 (1.11), 1.881 (1.08), 1.984(0.97), 2.006 (0.89), 2.022 (0.87), 2.053 (0.54), 2.085 (0.63), 2.329(0.55), 2.366 (0.77), 2.403 (0.62), 2.428 (0.65), 2.455 (1.02), 2.564(1.18), 2.583 (1.02), 2.612 (0.66), 2.666 (1.32), 2.689 (0.72), 2.710(0.66), 2.722 (0.67), 2.755 (0.54), 2.809 (0.49), 3.748 (14.53), 3.791(16.00), 3.854 (0.41), 3.862 (0.50), 4.113 (3.61), 4.156 (2.20), 4.173(2.21), 4.209 (0.59), 4.431 (0.55), 4.452 (1.11), 4.471 (0.60), 4.603(1.39), 4.628 (1.11), 4.661 (0.79), 4.680 (0.80), 6.892 (2.47), 6.913(2.61), 7.096 (1.38), 7.107 (1.47), 7.114 (2.17), 7.125 (2.21), 7.132(1.33), 7.142 (1.28), 7.226 (2.08), 7.244 (2.23), 7.290 (1.90), 7.308(2.06), 7.536 (4.09), 7.541 (4.95), 7.557 (5.15), 7.562 (4.72), 7.766(1.54), 7.780 (1.80), 7.784 (1.91), 7.800 (2.06), 7.805 (1.57), 7.819(1.51), 7.942 (3.89), 7.964 (3.53), 7.983 (4.24), 8.004 (3.73), 8.581(2.38), 8.586 (2.56), 8.591 (2.54), 8.595 (2.33), 9.014 (1.27), 9.019(1.30), 9.032 (2.36), 9.037 (2.29), 9.050 (1.39), 9.055 (1.30). LC-MS(method 2): R_(t) = 1.76 min; m/z = 503/505 (M + H)⁺. 87[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone (enantiomer 2)

from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and3,9-diazabicyclo[4.2.1]non-9-yl(6- methoxypyridin-2-yl)methanone(enantiomer 2) ¹H NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.008 (1.21), 1.235(1.01), 1.337 (0.70), 1.363 (0.73), 1.502 (0.54), 1.621 (1.60), 1.863(1.23), 1.985 (1.06), 2.085 (0.64), 2.328 (0.65), 2.366 (0.95), 2.392(0.75), 2.561 (1.25), 2.583 (0.99), 2.612 (0.65), 2.666 (1.30), 2.696(0.77), 2.710 (0.78), 2.757 (0.57), 2.804 (0.52), 3.748 (14.57), 3.791(16.00), 3.854 (0.62), 3.862 (0.55), 4.113 (3.54), 4.157 (2.20), 4.173(2.13), 4.209 (0.60), 4.432 (0.58), 4.452 (1.12), 4.472 (0.61), 4.603(1.51), 4.662 (0.82), 4.681 (0.79), 6.892 (2.57), 6.913 (2.71), 7.096(1.43), 7.107 (1.50), 7.114 (2.15), 7.124 (2.14), 7.132 (1.39), 7.142(1.27), 7.226 (2.02), 7.244 (2.18), 7.291 (1.90), 7.307 (1.99), 7.536(4.35), 7.541 (5.05), 7.557 (5.23), 7.562 (4.71), 7.766 (1.70), 7.780(1.92), 7.784 (1.92), 7.798 (2.08), 7.805 (1.61), 7.819 (1.55), 7.942(3.93), 7.964 (3.51), 7.983 (4.28), 8.005 (3.68), 8.582 (2.49), 8.585(2.67), 8.592 (2.57), 8.595 (2.36), 9.014 (1.32), 9.019 (1.31), 9.032(2.35), 9.037 (2.22), 9.050 (1.40), 9.055 (1.26). LC-MS (method 1):R_(t) = 0.92 min; m/z =503/505 (M + H)⁺.

Example 88 and Example 89[3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2-fluorophenyl)methanone(Enantiomers 1 and 2)

117 mg (240 μmol) of racemic[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](2-fluorophenyl)methanone(Example 69) were separated into the enantiomers by preparative HPLC ona chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm;mobile phase: n-heptane/ethanol 70:30 (v/v)+0.2% diethylamine; flowrate: 15 ml/min; UV detection: 235 nm; temperature: 50° C.]:

Example 88 (Enantiomer 1)

Yield: 56 mg

R_(t)=5.70 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/ethanol 70:30 (v/v)+0.2% diethylamine; flow rate: 1 ml/min;temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 2): R_(t)=1.62 min; m/z=489/491 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.19-1.34 (m, 0.5H), 1.35-1.47 (m,1.5H), 1.50-1.68 (m, 1H), 1.68-1.78 (m, 0.5H), 1.78-1.93 (m, 1H),1.94-2.20 (m, 2H), 2.31-2.45 (m, 1.5H), 2.56-2.69 (m, 1H), 2.71-2.86 (m,1H), 3.65-3.78 (m, 1H), 4.01-4.23 (m, 2H), 4.47-4.64 (m, 1H), 6.95-7.04(m, 1H), 7.19-7.37 (m, 4H), 7.43-7.49 (m, 1H), 7.49-7.57 (m, 2H), 7.60(dd, 1H), 7.87-8.02 (m, 2H), 8.49-8.70 (m, 1H).

Example 89 (Enantiomer 2)

Yield: 58 mg

R_(t)=6.60 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/ethanol 70:30 (v/v)+0.2% diethylamine; flow rate: 1 ml/min;temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 2): R_(t)=1.62 min; m/z=489/491 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.22-1.33 (m, 0.5H), 1.35-1.46 (m,1.5H), 1.50-1.68 (m, 1H), 1.69-1.78 (m, 0.5H), 1.79-1.92 (m, 1H),1.94-2.21 (m, 2H), 2.31-2.45 (m, 1.5H), 2.57-2.69 (m, 1H), 2.72-2.86 (m,1H), 3.66-3.79 (m, 1H), 4.04-4.22 (m, 2H), 4.49-4.62 (m, 1H), 6.95-7.03(m, 1H), 7.19-7.37 (m, 4H), 7.43-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.60(dd, 1H), 7.77-8.07 (m, 2H), 8.45-8.71 (m, 1H).

Example 90 and Example 91[3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone(Enantiomers 1 and 2)

195 mg (389 μmol) of racemic[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](6-methoxypyridin-2-yl)methanone(Example 70) were separated into the enantiomers by preparative HPLC ona chiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm×20 mm; mobilephase: n-heptane/ethanol 50:50 (v/v)+0.2% diethylamine; flow rate: 15ml/min; UV detection: 235 nm; temperature: 40° C.]:

Example 90 (Enantiomer 1)

Yield: 92 mg

R_(t)=7.65 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/ethanol 50:50 (v/v)+0.2% diethylamine; flow rate: 1 ml/min;temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 2): R_(t)=1.63 min; m/z=502/504 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.26-1.44 (m, 1H), 1.44-1.54 (m,0.5H), 1.56-1.68 (m, 1H), 1.69-1.92 (m, 2H), 1.95-2.13 (m, 1.5H),2.31-2.88 (m, 4H), 4.05-4.21 (m, 2H), 4.45 (t, 0.5H), 4.55-4.70 (m,1.5H), 6.90 (d, 1H), 6.97 (q, 1H), 7.20-7.34 (m, 2H), 7.52 (dd, 2H),7.60 (dt, 1H), 7.73-7.84 (m, 1H), 7.94 (dd, 2H), 8.61 (t, 1H).

Example 91 (Enantiomer 2)

Yield: 94 mg

R_(t)=8.93 min; chemical purity >99%; >99% ee

[column: Daicel Chiralpak IA, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/ethanol 50:50 (v/v)+0.2% diethylamine; flow rate: 1 ml/min;temperature: 50° C.; UV detection: 235 nm].

LC-MS (method 2): R_(t)=1.64 min; m/z=502/504 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.27-1.44 (m, 1H), 1.43-1.54 (m,0.5H), 1.56-1.69 (m, 1H), 1.69-1.79 (m, 0.5H), 1.79-1.91 (m, 1.5H),1.95-2.14 (m, 1.5H), 2.31-2.88 (m, 4H), 4.04-4.22 (m, 2H), 4.45 (t,0.5H), 4.55-4.70 (m, 1.5H), 6.90 (d, 1H), 6.97 (q, 1H), 7.19-7.35 (m,2H), 7.52 (dd, 2H), 7.60 (dt, 1H), 7.75-7.83 (m, 1H), 7.94 (dd, 2H),8.61 (t, 1H).

Analogously to Examples 13-16, the following compounds were preparedfrom the starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 92[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- LC-MS (methodyl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3- 2):fluoro-6-methoxypyridin-2-yl)methanone (racemate) R_(t) = 1.47 min;

m/z = 536/538 (M + H)⁺. from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and (3-fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (racemate) 93[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3- LC-MS (methodyl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3- 2):fluoro-6-methoxypyridin-2-yl)methanone (racemate) R_(t) = 1.67 min;

m/z = 537/539 (M + H)⁺. from2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3- carbaldehyde and(3-fluoro-6-methoxypyridin-2-yl)[8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl]methanone (racemate)

Analogously to Example 17, the following compounds were prepared fromthe starting materials specified in each case:

Example Name/Structure/Starting materials Analytical data 94[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- ¹H-NMR (500 MHz, DMSO-yl]methyl}-3,6-diazabicyclo[3.2.2]non-6-yl](3- d₆): δ [ppm] = 1.39-1.50(m, fluoro-6-methoxypyridin-2-yl)methanone 0.25H), 1.50-1.61 (m, 0.75H),(enantiomer 1) 1.61-1.84 (m, 2.75H), 1.87-

1.98 (m, 0.25H), 2.06 (br. s, 0.25H), 2.22-2.35 (m, 1H), 2.43-2.65 (m,1.75H, partially covered by DMSO signal), 2.73-2.88 (m, 1H), 2.96 (br.dd, 0.75H), 3.00-3.09 (m, 0.25H), 3.17-3.35 (m, 0.5H, partially coveredby H₂O signal), 3.39- 3.50 (m, 0.75H), 3.60 (br. d, 0.75H), 3.63-3.71(m, 3H), 3.83 (s, 0.75H), 4.00-4.14 (m, 2H), 4.54-4.62 (m, 0.25H), 6.88(dd, 0.75H), 6.92-7.03 (m, 1.25H), 7.26-7.36 (m, 1H), 7.49-7.56 (m, 2H),7.57-7.64 (m, 1H), 7.73 (t, 0.75H), 7.79 (t, 0.25H), 7.91-8.01 (m, 2H),8.54-8.63 (m, 1H). from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine- LC-MS(method 2): 3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non- R_(t) = 1.56min; m/z = 520/522 6-yl(3-fluoro-6-methoxypyridin-2-yl)methanone (M+H)⁺.hydrochloride (enantiomer 1) 95[3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3- ¹H-NMR (500 MHz, DMSO-yl]methyl}-3,6-diazabicyclo[3.2.2]non-6-yl](6- d₆): δ [ppm] = 1.42-1.59(m, methoxypyridin-2-yl)methanone (enantiomer 1) 1H), 1.60-1.85 (m,2.75H),

1.86-1.98 (m, 0.25H), 2.03- 2.11 (m, 0.25H), 2.23-2.31 (m, 0.75H),2.31-2.38 (m, 0.25H), 2.45-2.63 (m, 1H, partially covered by DMSOsignal), 2.72-2.88 (m, 1.75H), 2.93- 3.04 (m, 1H), 3.37-3.49 (m, 1H),3.53-3.67 (m, 3.25H), 3.85 (s, 0.75H), 3.98 (br. s, 0.75H), 4.04-4.14(m, 2H), 4.55 (br. s, 0.25H), 6.82 (d, 0.75H), 6.88 (d, 0.25H), 6.92-7.01 (m, 1H), 7.09 (d, 0.75H), 7.21 (d, 0.25H), 7.26-7.35 (m, 1H),7.49-7.57 (m, 2H), 7.57- 7.64 (m, 1H), 7.75 (dd, 0.75H), from2-(4-chlorophenyl)imidazo[1,2-a]pyridine- 7.81 (dd, 0.25H), 7.92-8.02(m, 3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non- 2H), 8.59 (d, 1H).6-yl(6-methoxypyridin-2-yl)methanone LC-MS (method 2): hydrochloride(enantiomer 1) R_(t) = 1.55 min; m/z = 502/504 (M + H)⁺. 96[3-{[2-(5-chloropyridin-2-yl)imidazo[1,2- ¹H-NMR (500 MHz, DMSO-a]pyridin-3-yl]methyl}-3,6- d₆): δ [ppm] = 1.36-1.95 (m,diazabicyclo[3.2.2]non-6-yl](3-fluoro-6- 4.25H), 1.99-2.08 (m, 0.25H),methoxypyridin-2-yl)methanone (enantiomer 1) 2.20-2.31 (m, 1H),2.41-2.60

(m, 1H, partially covered by DMSO signal), 2.77 (br. dd, 0.75H), 2.89(br. dd, 0.25H), 3.05 (br. dd, 1H), 3.14-3.29 (m, 0.5H), 3.41 (dd, 1H),3.52-3.64 (m, 4H), 3.83 (s, 0.75H), 4.41- 4.71 (m, 2.25H), 6.85 (dd,0.75H), 6.91-7.06 (m, 1.25H), 7.28-7.39 (m, 1H), 7.57-7.65 (m, 1H), 7.70(t, 0.75H), 7.80 (t, 0.25H), 7.96-8.03 (m, 1H), 8.17-8.25 (m, 1H),8.48-8.59 (m, 1H), 8.67 (d, 1H). LC-MS (method 2): R_(t) = 1.20 min; m/z= 521/523 (M + H)⁺. from 2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridine-3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non-6-yl(3-fluoro-6- methoxypyridin-2-yl)methanonehydrochloride (enantiomer 1) 97 [3-{[2-(4-chlorophenyl)imidazo[1,2-¹H-NMR (500 MHz, DMSO- a]pyrimidin-3-yl]methyl}-3,6- d₆): δ [ppm] =1.37-1.86 (m, diazabicyclo[3.2.2]non-6-yl](3-fluoro-6- 4H), 1.87-1.98(m, 0.25H), methoxypyridin-2-yl)methanone (enantiomer 1) 2.06 (br. s,0.25H), 2.21-2.35

(m, 1H), 2.41-2.62 (m, 1.5H, partially covered by DMSO signal),2.72-2.89 (m, 1H), 2.97 (br. dd, 0.75H), 3.05 (br. dd, 0.25H), 3.16-3.35(m, 0.5H, partially covered by H₂O signal), 3.44 (dd, 0.75H), 3.55- 3.70(m, 3.75H), 3.82 (s, 0.75H), 4.01-4.17 (m,2H), 4.58 (br. t, 0.25H), 6.88(dd, 0.75H), 6.95 (dd, 0.25H),7.07- 7.19 (m, 1H), 7.52-7.62 (m, 2H),7.69-7.84 (m, 1H), 7.93- 8.04 (m, 2H), 8.54-8.63 (m, 1H), 8.96-9.07 (m,1H). LC-MS (method 2): R_(t) = 1.75 min; m/z = 521/523 (M + H)⁺. from2-(4-chlorophenyl)imidazo[1,2- a]pyrimidine-3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non-6-yl(3-fluoro-6- methoxypyridin-2-yl)methanonehydrochloride (enantiomer 1) 98 [3-{[2-(4-chlorophenyl)imidazo[1,2-¹H-NMR (500 MHz, DMSO- a]pyrimidin-3-yl]methyl}-3,6- d₆): δ [ppm] =1.42-1.86 (m, diazabicyclo[3.2.2]non-6-yl](6-methoxypyridin- 4H),1.86-1.98 (m, 0.25H), 2-yl)methanone (enantiomer 1) 2.07 (br. s, 0.25H),2.26 (br. s,

0.75H), 2.34 (br. d, 0.25H), 2.57 (br. d, 0.75H), 2.70-2.88 (m, 1.75H),2.94-3.05 (m, 1H), 3.37-3.48 (m, 1H), 3.53-3.66 (m, 3.25H), 3.85 (s,0.75H), 3.97 (br.s, 0.75H), 4.02-4.16 (m, 2H), 4.54 (br. s, 0.25H), 6.82(d, 0.75H), 6.89 (d, 0.25H), 7.06-7.22 (m, 2H), 7.51-7.61 (m, 2H),7.71-7.85 (m, 1H), 7.94-8.02 (m, 2H), 8.54-8.62 (m, 1H), 8.98-9.06 (m,1H). LC-MS (method 2): R_(t) = 1.74 min; m/z = 503/505 (M + H)⁺. from2-(4-chlorophenyl)imidazo[1,2- a]pyrimidine-3-carbaldehyde and 3,6-diazabicyclo[3.2.2]non-6-yl(6-methoxypyridin- 2-yl)methanonehydrochloride (enantiomer 1) 99(3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4- ¹H-NMR (500 MHz, DMSO-chlorophenyl)imidazo[1,2-a]pyrimidin-3- d₆): δ [ppm] = 1.29-2.05 (m,yl]methyl}-3,9-diazabicyclo[4.2.1]non-9- 5.75H), 2.07-2.19 (m, 0.5H),yl)methanone (racemate) 2.27-2.35 (m, 0.5H), 2.36-2.46

(m, 0.5H), 2.46-2.64 (m, 1.75H, partially covered by DMSO signal),2.74-2.86 (m, 1H), 3.65-3.74 (m, 1H), 3.77 (s, 1.75H), 3.82 (s, 1.25H),4.08-4.26 (m, 2H), 4.50-4.61 (m, 1H), 6.92 (dd, 1H), 7.10- 7.18 (m, 1H),7.51-7.61 (m, 2H), 7.87 (dd, 1H), 7.93 (d, 1H), 8.01 (d, 1H), 8.56-8.63(m, 1H), 9.02-9.11 (m, 1H). LC-MS (method 1): R_(t) = 0.92 min; m/z =537/539 (M + H)⁺ (Rotamer 1), R_(t) = 0.94 min; m/z = 537/539 (M + H)⁺(Rotamer 2). from 2-(4-chlorophenyl)imidazo[1,2-a]pyrimidine-3-carbaldehyde and (3-chloro-6- methoxypyridin-2-yl)(3,9-diazabicyclo[4.2.1]non-9-yl)methanone hydrochloride (racemate) 100(3-chloro-6-methoxypyridin-2-yl)(3-{[2-(5- ¹H-NMR (500 MHz, DMSO-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3- d₆): δ [ppm] = 1.21-1.68 (m,yl]methyl}-3,9-diazabicyclo[4.2.1]non-9- 3.25H), 1.69-1.88 (m, 1.75H),yl)methanone (racemate) 1.89-2.05 (m, 1H), 2.06-2.19

(m, 0.5H), 2.37 (br. d, 0.5H), 2.44-2.62 (m, 1.5H, partially covered byDMSO signal), 2.64-2.73 (m, 0.5H), 2.87-3.02 (m, 1H), 3.63-3.72 (m, 1H),3.77 (s, 1.6H), 3.87 (s, 1.4H), 4.40-4.59 (m, 2H), 4.61-4.86 (m, 1H),6.91 (dd, 1H), 6.98- 7.05 (m, 1H), 7.31-7.40 (m, 1H), 7.62 (dd, 1H),7.87 (dd, 1H), 8.00 (td, 1H), 8.21 (t, 1H), 8.55-8.65 (m, 1.5H), 8.69(d, 0.5H). LC-MS (method 1): R_(t) = 0.72 min; m/z = 537/539 (M + H)⁺.from 2-(5-chloropyridin-2-yl)imidazo[1,2- a]pyridine-3-carbaldehyde and(3-chloro-6- methoxypyridin-2-yl)(3,9-diazabicyclo[4.2.1]non-9-yl)methanone hydrochloride (racemate)

Example 101 (3-Chloro-6-methoxypyridin-2-yl)[3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone(Enantiomer 1)

Under argon,(3-chloro-6-methoxypyridin-2-yl)[(3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone-hydrogenchloride (1/1) (Enantiomer 1) (90 mg, 270 μmol) was taken up in 2 ml ofTHF, and 98 μl (0.57 mmol) of N,N-diisopropylethylamine were added. Thereaction solution was then stirred at room temperature for 2 hours.Subsequently, the reaction solution was concentrated to dryness and theresidue obtained was then taken up in 2 ml of THF, and2-[4-(propan-2-yl)phenyl]imidazo[1,2-a]pyrimidine-3-carbaldehyde (60.0mg, 230 μmol), 0.25 ml of dichloromethane and acetic acid (32 μl, 570μmol) were added. Sodium triacetoxyborohydride (72 mg, 340 μmol) wasthen added and the mixture was stirred at room temperature overnight.After the addition of saturated ammonium chloride solution, the reactionmixture was evaporated to dryness. The resulting residue was then takenup in ethyl acetate and washed with a saturated sodium carbonatesolution, and the organic phase obtained was subsequently evaporated todryness. The reaction mixture was then separated into its componentsdirectly by preparative HPLC (Method 9). The main component obtained wassubsequently purified by column chromatography (silica gel; mobile phaseethyl acetate). This gave 56 mg (100% pure, 0.1 mmol, 46% of theory) ofthe title compound.

LC-MS (Method 2): R_(t)=1.95/1.98 min; m/z=545/547 (M+H)⁺.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.25 (d, 6H), 1.31-1.42 (m, 1H),1.44-1.69 (m, 2H), 1.71-1.88 (m, 1.5H), 1.92-2.03 (m, 1H), 2.07-2.18 (m,0.5H), 2.26-2.44 (m, 1H), 2.52-2.60 (m, 2H), 2.81 (br s, 1H), 2.95(quin, 1H), 3.67-3.74 (m, 1H), 3.78 (s, 1.5H), 3.82 (s, 1.5H), 4.10-4.23(m, 2H), 4.53-4.59 (m, 1H), 6.92 (dd, 1H), 7.12 (dd, 1H), 7.36 (br d,1H), 7.38 (br d, 1H), 7.79 (d, 1H), 7.87 (d, 2H), 8.57 (s, 1H), 9.03 (t,1H).

Analogously to Example 101, the following compounds were prepared fromthe starting materials stated in each case:

Example Name/Structure/Starting materials Analytical data 102(3-Fluoro-6-methoxypyridin-2-yl)[3-{[2-(4- ¹H NMR (500 MHz, DMSO-d₆)isopropylphenyl)imidazo[1,2-a]pyrimidin-3- δ ppm 1.25 (d, 6H), 1.30-1.41yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9- (m, 1H), 1.44-2.17 (m, 5H),yl]methanone (Enantiomer 1) 2.33-2.47 (m, 2H), 2.52-2.64

(m, 1H), 2.76-2.86 (m, 1H), 2.95 (dt, 1H), 3.78 (d, 3H), 3.84-3.93 (m,1H), 4.10-4.23 (m, 2H), 4.52-4.59 (m, 1H), 6.94 (ddd, 1H), 7.12 (ddd, 1H), 7.37 (dd, 2H), 7.74-7.82 (m, 2H), 7.87 (d, 1H), 8.57 (dd, 1H), 9.03(ddd, 1H). LC-MS (Method 2): R_(t) = 1.88 min; MS (ESIpos): m/z = 529(M + H)⁺ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2-a]pyrimidine-3-carbaldehyde and [3,9-diazabicyclo[4.2.1]nonan-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 1) 103(3-Fluoro-6-methoxypyridin-2-yl)[3-{[2-(4- ¹H NMR (500 MHz, DMSO-d₆)isopropylphenyl)imidazo[1,2-a]pyrimidin-3- δ ppm 1.25 (d, 6H), 1.31-1.40yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9- (m, 1H), 1.43-2.19 (m, 5H),yl]methanone (Enantiomer 2) 2.30-2.47 (m, 2H), 2.55-2.64

(m, 1H), 2.76-2.86 (m, 1H), 2.95 (dt, 1H), 3.78 (d, 3H), 3.84-3.93 (m,1H), 4.09-4.23 (m, 2H), 4.52-4.59 (m, 1H), 6.94 (ddd, 1H), 7.12 (ddd, 1H), 7.37 (dd, 2H), 7.74-7.82 (m, 2H), 7.87 (d, 1H), 8.57 (dd, 1H), 9.03(ddd, 1H) LC-MS (Method 2): R_(t) = 1.87 min; MS (ESIpos): m/z = 529(M + H)⁺ from 2-[4-(propan-2-yl)phenyl]imidazo[1,2-a]pyrimidine-3-carbaldehyde and [3,9-diazabicyclo[4.2.1]nonan-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 2) 104[3-{[2-(4-Isopropylphenyl)imidazo[1,2- ¹H NMR (500 MHz, DMSO-d₆)a]pyrimidin-3-yl]methyl}-3,9- δ ppm 1.25 (dd, 6H), 1.30-diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin- 1.42 (m, 1H), 1.45-1.56(m, 2-yl)methanone (Enantiomer 1) 0.5H), 1.63 (br s, 1H), 1.70-

1.93 (m, 2H), 1.96-2.13 (m, 1.5H), 2.33-2.47 (m, 1H), 2.52-2.68 (m, 2H),2.70-2.87 (m, 1H), 2.91-2.99 (m, 1H), 3.74 (s, 1.5H), 3.79 (s, 1.5H),4.08-4.20 (m, 2H), 4.46 (t, 0.5 H), 4.55-4.72 (m, 1.5H), 6.88- 6.92 (m,1H), 7.07-7.12 (m, 1H), 7.22-7.31 (m, 1H), 7.36 (dd, 2H), 7.77-7.87 (m,3H), 8.54-8.58 (m, 1H), 9.01 (t, 1 H) LC-MS (Method 2): R_(t) = 1.89min; MS (ESIpos): m/z = 511 (M + H)⁺ from2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and[3,9- diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin-2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 1) 105[(3-{[2-(4-Isopropylphenyl)imidazo[1,2- ¹H NMR (500 MHz, DMSO-d₆)a]pyrimidin-3-yl]methyl}-3,9- δ ppm 1.25 (dd, 6H), 1.30-diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin- 1.44 (m, 1H), 1.45-1.54(m, 2-yl)methanone (Enantiomer 2) 0.5H), 1.58-1.67 (m, 1H),

1.69-1.92 (m, 2H), 1.96-2.11 (m, 1.5H), 2.32-2.44 (m, 1H), 2.52-2.68 (m,2H), 2.71-2.88 (m, 1H), 2.95 (quind, 1H), 3.74 (s, 1.5H), 3.79 (s,1.5H), 4.09-4.20 (m, 2H), 4.46 (t, 0.5 H), 4.58-4.67 (m, 1.5H), 6.90(ddd, 1H), 7.07-7.12 (m, 1H), 7.21-7.32 (m, 1H), 7.36 (dd, 2 H),7.77-7.87 (m, 3H), 8.55- 8.58 (m, 1H), 9.01 (t, 1H) LC-MS (Method 2):R_(t) = 1.89 min; MS (ESIpos): m/z = 511 (M + H)⁺ from2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and[3,9- diazabicyclo[4.2.1]nonan-9-yl](6-methoxypyridin-2-yl)methanone-hydrogen chloride (1/1) (Enantiomer 2) 106(3-Chloro-6-methoxypyridin-2-yl)[3-{[2-(4- 1H NMR (500 MHz, DMSO-isopropylphenyl)imidazo[1,2-a]pyrimidin-3- d6) δ ppm 1.25 (d, 6H), 1.30-yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9- 1.42 (m, 1H), 1.44-1.69 (m, 2yl]methanone (Enantiomer 2) H), 1.72-1.88 (m, 1.5H), 1.91-

2.03 (m, 1H), 2.07-2.20 (m, 0.5H), 2.27-2.45 (m, 1H), 2.52-2.60 (m, 2H),2.81 (br s, 1H), 2.95 (quin, 1H), 3.67- 3.74 (m, 1H), 3.78 (s, 1.5H),3.82 (s, 1.5H), 4.10-4.23 (m, 2 H), 4.53-4.59 (m, 1H), 6.92 (dd, 1H),7.12 (dd, 1H), 7.36 (br d, 1H), 7.38 (br d, 1H), 7.79 (d, 1H), 7.87 (dt,2H), 8.57 (s, 1H), 9.03 (ddd, 1H) LC-MS (Method 2): Rt = 1.94/1.98 min;MS (ESIpos): m/z = 545/547 (M + H)⁺ from2-[4-(propan-2-yl)phenyl]imidazo[1,2- a]pyrimidine-3-carbaldehyde and(3-chloro-6- methoxypyridin-2-yl)[(3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone- hydrogen chloride (1/1)(Enantiomer 2)

B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY

The pharmacological activity of the compounds of the invention can bedemonstrated by in vitro and in vivo studies as known to the personskilled in the art. The application examples which follow describe thebiological action of the compounds of the invention, without restrictingthe invention to these examples.

B-1. In Vitro Electrophysiological Analysis of the Human TASK-1 andTASK-3 Channels Via Two-Electrode Voltage Clamp Technique in Xenopuslaevis Oocytes

Xenopus laevis oocytes were selected as described elsewhere by way ofillustration [Decher et al., FEBS Lett. 492, 84-89 (2001)].Subsequently, the oocytes were injected with 0.5-5 ng of a cRNA solutioncoding for TASK-1 or TASK-3. For the electrophysiological analysis ofthe channel proteins expressed in the oocytes, the two-electrode voltageclamp technique [Stühmer, Methods Enzymol. 207, 319-339 (1992)] wasused. The measurements were conducted as described [Decher et al., FEBSLett. 492, 84-89 (2001)] at room temperature (21-22° C.) using a TurboTEC 10CD amplifier (NPI), recorded at 2 kHz and filtered with 0.4 kHz.Substance administration was performed using a gravitation-drivenperfusion system. Here, the oocyte is located in a measuring chamber andexposed to the solvent stream of 10 ml/min. The level in the measuringchamber is monitored and regulated by sucking off the solution using aperistaltic pump.

Table 1 below shows the half-maximum inhibition, determined in thistest, of the human TASK-1 channel (IC₅₀) by representative workingexamples of the invention:

TABLE 1 Example TASK-1 TASK-3 No. IC₅₀ [nM] IC₅₀ [nM] 11 11.4 ± 2.2 4.8± 0.4 12 17.6 ± 2.2  13 ± 0.9 13 40.3 ± 3.4 23.5 ± 5.9 14 20.6 ± 3.117.3 ± 1.6 15 7.54 ± 1.4 15.5 ± 1.5 93 35.1 ± 3.5 41.8 ± 8.0

From the data in Table 1 it is evident that the human TASK-3 channel isblocked by compounds of the present invention.

B-2. Inhibition of Recombinant TASK-1 and TASK-3 In Vitro

The investigations on the inhibition of the recombinant TASK-1 andTASK-3 channels were conducted using stably transfected CHO cells. Thecompounds of the invention were tested here with administration of 40 mMof potassium chloride in the presence of a voltage-sensitive dye usingthe method described in detail in the following references [Whiteaker etal., Validation of FLIPR membrane potential dye for high-throughputscreening of potassium channel modulators, J. Biomol. Screen. 6 (5),305-312 (2001); Molecular Devices FLIPR Application Note: Measuringmembrane potential using the FLIPR® membrane potential assay kit onFluorometric Imaging Plate Reader (FLIPR®) systems,http://www.moleculardevices.com/reagents-supplies/assay-kits/ion-channels/flipr-membrane-potential-assay-kits].The activity of the test substances was determined as their ability toinhibit a depolarization induced in the recombinant cells by 40 mMpotassium chloride. The concentration which can block half of thisdepolarization is referred to as IC₅₀.

Table 2 below lists the IC₅₀ values from this assay determined forindividual working examples of the invention (some as mean values frommultiple independent individual determinations):

TABLE 2 Example TASK-1 TASK-3 No. IC₅₀ [nM] IC₅₀ [nM] 11 113 1.1 12 60.52.5 13 1000 2.2 14 760 4.5 15 250 7.3 16 1700 65 17 3300 15 18 1600 16719 13500 580 20 3350 197 21 18000 140 22 27000 370 23 3000 24 24 3100 2425 1100 11 26 830 6.9 27 150 3 28 280 5.6 29 660 4.4 30 2300 220 31 91047 32 130 4.1 33 2600 110 34 4100 200 35 24000 500 36 30000 1000 3730000 1000 38 250 4 39 370 13 40 3300 29 41 2200 160 43 2500 250 45 2900170 46 16000 1000 47 3100 180 48 12000 430 49 5500 540 50 2500 440 511100 110 52 3800 140 53 1300 380 54 780 290 55 4000 1000 56 8500 1000 576200 2000 58 2900 920 59 1100 680 60 5200 1000 61 9400 1000 62 8400 100063 8400 800 64 7200 1800 65 1400 220 66 180 19 67 3400 370 68 230 31 691400 62 70 305 4.7 71 740 31 72 120 5.1 73 99 5 74 5000 200 75 2300 7776 1400 66 77 3300 270 78 220 5. 3 79 290 11 80 4500 93 81 590 9.2 82 301.4 83 410 17 84 350 25 85 6300 370 86 340 28 87 1600 210 88 91 1.6 89310 19 90 43 2.8 91 290 5.5 92 85 2.5 93 340 12 94 3200 110 95 4900 71099 290 34 100 370 42 101 400 16 102 170 36 103 1400 200 104 600 31 1053700 370 106 1300 140

From the data in Table 2 it is evident that both TASK-1 and inparticular TASK-3 are blocked. The results in Table 2 thus confirm themechanism of action of the compounds according to the invention as dualTASK-1/3 inhibitors.

B-3. Animal Model of Obstructive Sleep Apnoea in the Pig

Using negative pressure, it is possible to induce collapse and thusobstruction of the upper respiratory tract in anaesthetized,spontaneously breathing pigs [Wirth et al., Sleep 36, 699-708 (2013)].

German Landrace pigs are used for the model. The pigs are anaesthetizedand tracheotomized. One cannula each is inserted into the rostral andthe caudal part of the trachea. Using a T connector, the rostral cannulais connected on the one hand to a device generating negative pressuresand on the other hand to the caudal cannula. Using a T connector, thecaudal cannula is connected to the rostral cannula and to a tube whichallows spontaneous breathing circumventing the upper respiratory tract.By appropriate closing and opening of the tubes it is thus possible forthe pig to change from normal nasal breathing to breathing via thecaudal cannula during the time when the upper respiratory tract isisolated and connected to the device for generating negative pressures.The muscle activity of the Musculus genioglossus is recorded byelectromyogram (EMG).

At certain points in time, the collapsibility of the upper respiratorytract is tested by having the pig breathe via the caudal cannula andapplying negative pressures of −50, −100 and −150 cm water head (cm H₂O)to the upper respiratory tract. This causes the upper respiratory tractto collapse, which manifests itself in an interruption of the airflowand a pressure drop in the tube system. This test is conducted prior tothe administration of the test substance and at certain intervals afterthe administration of the test substance. An appropriately effectivetest substance can prevent this collapse of the respiratory tract in theinspiratory phase.

After changeover from nasal breathing to breathing via the caudalcannula, it is not possible to measure any EMG activity of the Musculusgenioglossus in the anaesthetized pig. As a further test, the negativepressure at which EMG activity restarts is then determined. Thisthreshold value is, if a test substance is effective, shifted to morepositive values. The test is likewise conducted prior to theadministration of the test substance and at certain intervals after theadministration of the test substance. Administration of the testsubstance can be intranasal, intravenous, subcutaneous, intraperitonealor intragastral.

C. WORKING EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted to pharmaceuticalpreparations as follows:

Tablet:

Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate),50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound of the invention, lactose and starch isgranulated with a 5% solution (w/w) of the PVP in water. The granulesare dried and then mixed with the magnesium stearate for 5 minutes. Thismixture is compressed using a conventional tableting press (see abovefor format of the tablet). The guide value used for the pressing is apressing force of 15 kN.

Suspension for Oral Administration:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g ofwater.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol; the compound of the invention isadded to the suspension. The water is added while stirring. The mixtureis stirred for about 6 h until the swelling of the Rhodigel is complete.

Solution for Oral Administration:

Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 gof polyethylene glycol 400. 20 g of oral solution correspond to a singledose of 100 mg of the compound of the invention.

Production:

The compound of the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirringoperation is continued until dissolution of the compound of theinvention is complete.

i.v. Solution:

The compound of the invention is dissolved in a concentration below thesaturation solubility in a physiologically acceptable solvent (e.g.isotonic saline solution, glucose solution 5% and/or PEG 400 solution30%). The solution is subjected to sterile filtration and dispensed intosterile and pyrogen-free injection vessels.

Solution for Nasal Administration:

The compound of the invention is dissolved in a concentration below thesaturation solubility in a physiologically acceptable solvent (e.g.purified water, phosphate buffer, citrate buffer). The solution maycontain further additives for isotonization, for preservation, foradjusting the pH, for improvement in the solubility and/or forstabilization.

The invention claimed is:
 1. A compound of formula (I)

wherein the ring Q is a bridged 1,4-diazepane cycle of the formula

wherein * denotes the bond to the adjacent methylene group and ** thebond to the carbonyl group; A is CH or N, D is CH or N, R¹ is halogen,cyano, (C₁-C₄)-alkyl, cyclopropyl or cyclobutyl, wherein (C₁-C₄)-alkylis optionally up to trisubstituted by fluorine, and cyclopropyl andcyclobutyl are optionally up to disubstituted by fluorine; and R² is(C₄-C₆)-cycloalkyl wherein a ring CH₂ group is optionally replaced by—O—; or R² is a phenyl group of the formula (a), a pyridyl group of theformula (b) or (c) or an azole group of the formula (d), (e), (f) or(g),

wherein *** marks the bond to the adjacent carbonyl group; and R³ ishydrogen, fluorine, chlorine, bromine or methyl; R⁴ is hydrogen,fluorine, chlorine, bromine, cyano, (C₁-C₃)-alkyl or (C₁-C₃)-alkoxy,wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxy are optionally up totrisubstituted by fluorine; R⁵ is hydrogen, fluorine, chlorine, bromineor methyl, R⁶ is hydrogen, (C₁-C₃)-alkoxy, cyclobutyloxy,oxetan-₃-yloxy, tetrahydrofuran-₃-yloxy, tetrahydro-₂H-pyran-₄-yloxy,mono-(C₁-C₃)-alkylamino, di-(C₁-C₃)-alkylamino or (C₁-C₃)-alkylsulfanyl,wherein (C₁-C₃)-alkoxy is optionally up to trisubstituted by fluorine;R⁷ is hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl or(C₁-C₃)-alkoxy; R^(8A) and R^(8B) are identical or different and areindependently hydrogen, fluorine, chlorine, bromine, (C₁-C₃)-alkyl,cyclopropyl or (C₁-C₃)-alkoxy, wherein (C₁-C₃)-alkyl and (C₁-C₃)-alkoxyare optionally up to trisubstituted by fluorine; R⁹ is hydrogen,(C₁-C₃)-alkyl or amino; and Y is O or S; or R² is an —OR¹⁰ or —NR¹¹R¹²group wherein R¹⁰is (C₁-C₆)-alkyl, (C₄-C₆)-cycloalkyl or[(C₃-C₆)-cycloalkyl]methyl; R¹¹ is hydrogen or (C₁-C₃)-alkyl; and R¹² is(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or benzyl, wherein(C₁-C₆)-alkyl is optionally up to trisubstituted by fluorine, and wherephenyl and the phenyl group in benzyl is optionally up to trisubstitutedby identical or different radicals selected from the group consisting offluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy andtrifluoromethoxy; or R¹¹ and R¹² are attached to one another and,together with the nitrogen atom to which they are bonded, form apyrrolidine, piperidine, morpholine or thiomorpholine ring, or a salt, asolvate, or a solvate of the salt thereof.
 2. The compound of formula(I) according to claim 1, wherein the ring Q is a bridged 1,4-diazepanecycle of the formula

wherein * denotes the bond to the adjacent methylene group and ** thebond to the carbonyl group; A is CH or N; D is CH or N; R¹ is fluorine,chlorine, bromine, methyl, isopropyl, tert-butyl, cyclopropyl orcyclobutyl; and R² is cyclobutyl, cyclopentyl or cyclohexyl; or R² is aphenyl group of the formula (a), a pyridyl group of the formula (b) oran azole group of the formula (d), (e), (f) or (g),

wherein *** marks the bond to the adjacent carbonyl group; and R³ ishydrogen, fluorine or chlorine; R⁴ is fluorine, chlorine, cyano,(C₁-C₃)-alkyl, (C₁-C₃)-alkoxy or trifluoromethoxy; R⁵ is hydrogen,fluorine, chlorine, bromine or methyl; R⁶ is (C₁-C₃)-alkoxy,cyclobutyloxy or (C₁-C₃)-alkylsulfanyl, wherein (C₁-C₃)-alkoxy may be upto trisubstituted by fluorine; R^(8A) and R^(8B) are identical ordifferent and are independently hydrogen, chlorine, bromine,(C₁-C₃)-alkyl or cyclopropyl, wherein (C₁-C₃)-alkyl may be up totrisubstituted by fluorine; R⁹ is methyl or amino; and Y is O or S, or asalt, a solvate, or a solvate of the salt thereof.
 3. The compound offormula (I) according to claim 1, wherein the ring Q is a bridged1,4-diazepane cycle of the formula

wherein * denotes the bond to the adjacent methylene group and ** thebond to the carbonyl group; A is CH or N; D is CH or N; R¹ is chlorine,bromine, isopropyl or cyclopropyl; and R² is cyclopentyl or cyclohexyl;or R² is a phenyl group of the formula (a), a pyridyl group of theformula (b) or an azole group of the formula (g),

wherein *** marks the bond to the adjacent carbonyl group; and R³ ishydrogen, fluorine or chlorine; R⁴ is fluorine, chlorine, methyl,isopropyl, methoxy or ethoxy; R⁵ is hydrogen, fluorine, chlorine,bromine or methyl; R⁶ is methoxy, difluoromethoxy, trifluoromethoxy,isopropoxy, cyclobutyloxy or methylsulfanyl; and R⁹ is methyl or amino,or a salt, a solvate, or a solvate of the salt thereof.
 4. Apharmaceutical composition comprising a compound according to claim 1 incombination with one or more inert, nontoxic, pharmaceutically suitableexcipients.
 5. A pharmaceutical combination comprising a compoundaccording to claim 1 in combination with one or more further activecompounds selected from the group consisting of respiratory stimulants,psychostimulating compounds, serotonin reuptake inhibitors,noradrenergic, serotonergic and tricyclic antidepressants, sGCstimulators, mineralocorticoid receptor antagonists, antiinflammatorydrugs, immunomodulators, immunosuppressives and cytotoxic drugs.
 6. Amethod for treatment of respiratory disorders, sleep-related respiratorydisorders, obstructive sleep apnoeas, central sleep apnoeas, snoring, orcardiac arrhythmias, comprising administering to a human or animal inneed thereof an effective amount of a compound of formula (I) accordingto claim
 1. 7. The method of claim 6, wherein the method is a method fortreatment of respiratory disorders.
 8. The method of claim 6, whereinthe method is a method for treatment of sleep-related respiratorydisorders.
 9. A method for treatment of respiratory disorders,sleep-related respiratory disorders, obstructive sleep apnoeas, centralsleep apnoeas, snoring, or cardiac arrhythmias, in a human or animal inneed thereof, comprising administering an effective amount of at leastone compound according to claim 1 to the human or animal.
 10. The methodof claim 9, wherein the method is a method for treatment of respiratorydisorders.
 11. The method of claim 9, wherein the method is a method fortreatment of sleep-related respiratory disorders.
 12. A method fortreatment of respiratory disorders, sleep-related respiratory disorders,obstructive sleep apnoea, central sleep apnoea, snoring, or cardiacarrhythmias, comprising administering to a human or animal in needthereof an effective amount of a pharmaceutical composition according toclaim
 4. 13. The method of claim 12, wherein the method is a method fortreatment of respiratory disorders.
 14. The method of claim 12, whereinthe method is a method for treatment of sleep-related respiratorydisorders.
 15. A method for treatment of respiratory disorders,sleep-related respiratory disorders, obstructive sleep apnoeas, centralsleep apnoeas, snoring, or cardiac arrhythmias, comprising administeringto a human or animal in need thereof an effective amount of apharmaceutical combination according to claim
 5. 16. The method of claim15, wherein the method is a method for treatment of respiratorydisorders.
 17. The method of claim 15, wherein the method is a methodfor treatment of sleep-related respiratory disorders.
 18. A process forpreparing a compound of formula (I) according to claim 1, comprisingreacting a compound of formula (II)

wherein A, D and R¹ are as defined in claim 1, in the presence of asuitable reducing agent either [A] with a compound of formula (III)

wherein R² and the ring Q are as defined in claim 1, to give a compoundof formula (I); or [B] with a protected diazabicyclic system of formula(IV)

wherein the ring Q is as defined in claim 1, and PG is a suitable aminoprotecting group, at first to give a compound of formula (V)

wherein A, D, PG, R¹ and the ring Q are as defined above, then removingthe protecting group PG to give a compound of formula (VI), and reactingthe resulting compound of formula (VI)

wherein A, D, R¹ and the ring Q are as defined above, depending on thespecific meaning of the R² radical, [B-1] with a carboxylic acid of theformula (VII)

wherein R^(2A) is (C₄-C₆)-cycloalkyl wherein a ring CH₂ group isoptionally replaced by —O—, or is a phenyl group of the formula (a), apyridyl group of the formula (b) or (c) or an azole group of the formula(d), (e), (f) or (g), as defined in claim 1, with activation of thecarboxylic acid function in (VII), or with the corresponding acidchloride of the formula (VIII)

wherein R^(2A) is as defined above, to give a compound of the formula(I-A)

wherein A, D, R¹, R^(2A) and the ring Q are as defined above; or [B-2]with a chloroformate or carbamoyl chloride of the formula (IX)

wherein R^(2B) is the —OR¹⁰ or —NR^(11A)R¹² group wherein R¹⁰ and R¹²are as defined in claim 1, and R^(11A) has the definition of R¹¹ inclaim 1, but is not hydrogen, to give a compound of the formula (I-B)

wherein A, D, R¹, R^(2B) and the ring Q are as defined above; or [B-3]with an isocyanate of the formula (X)R¹²—N═C═O  (X), wherein R¹² is as defined in claim 1, to give a compoundof formula (I-C)

wherein A, D, R¹, R¹² and the ring Q are as defined above, andoptionally separating the compound of formula (I), (I-A), (I-B) or (I-C)into its enantiomers and/or diastereomers and/or optionally convertingthe compound of formula (I), (I-A), (I-B) or (I-C) with the appropriate(i) solvents and/or (ii) acids to a salt, a solvate, or a solvate of thesalt thereof.
 19. The process of claim 18, wherein the suitable aminoprotecting group PG is tert-butoxycarbonyl, benzyloxycarbonyl or(9H-fluoren-9-ylmethoxy)carbonyl.